JP6987384B2 - Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment - Google Patents

Description

Related Applications This application claims the interests and priority of US Provisional Patent Application No. 62 / 182,336 (filed June 19, 2015). The above application is incorporated herein by reference in its entirety.
Statement of official development assistance
The present invention is provided with government assistance under grant number U01 AG041140 awarded by the National Institutes of Health (NIH), a US National Institutes of Health (NIA) department, which is an agency of the United States Government. It was conducted. The United States Government reserves certain rights in the present invention.

INDUSTRIAL APPLICABILITY The present invention relates to compounds, compositions and methods for treating said cognitive deficits in subjects who require or are at risk of treating cognitive deficits associated with central nervous system (CNS) disorders.

Background of the Invention Cognitive ability may be impaired as a result of normal aging or as a result of central nervous system disorders.

For example, a significant elderly population experiences more than the typical cognitive decline in normal aging. Such age-related loss of cognitive function is clinically characterized by a progressive loss of memory, cognition, reasoning and judgment. Mild cognitive impairment (MCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD) or similar clinical classifications are associated with such age-related loss of cognitive function. .. According to some estimates, more than 16 million people in the United States alone have AAMI (Barker et al., 1995), and it is estimated that 550-7 million people over the age of 65 in the United States have MCI (MCI). Plusman et al., 2008).

Cognitive impairment includes other central nervous system (CNS) disorders such as dementia, Alzheimer's disease (AD), precursor AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder (especially manic disease), muscle. Also associated with atrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorders, vulnerable X disorders, Let syndrome, compulsive behavior and substance addiction. ..

Therefore, effective treatment of cognitive impairment associated with central nervous system (CNS) disorders, and eg age-related cognitive impairment, MCI, forgetfulness MCI, AAMI, ARCD, dementia, AD, precursor AD, PTSD, integration. Ataxia or bipolar disorder (especially manic disease), muscular atrophic lateral sclerosis (ALS), cognitive impairment associated with cancer treatment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder Needs effective treatment to improve cognitive function in patients diagnosed with or at risk of developing similar central nervous system (CNS) disorders with, let syndrome, compulsive behavior and substance addiction, and cognitive impairment Has been done.

GABA _A receptor (GABA _A R) is the neurotransmitter γ- aminobutyric acid (GABA) gated Cl- form a transparent channel, different subunits (α1~6, β1~3, γ1~3, δ , ε , Π, θ) is an aggregate of pentamers from the pool. Various GABA _A subtypes mediate a variety of pharmacological effects, including anxiety disorders, epilepsy, insomnia, pre-anesthetic sedation and muscle relaxation.

Various studies have demonstrated that reduced GABA signaling is associated with various CNS disorders with cognitive impairment. In particular, .alpha.5-containing GABA A _R is a relatively low density in the brain of mammals, it plays a role in modifications of learning and memory. Previous studies have demonstrated that in rats with age-related cognitive decline _{, expression of the α5 subunit of the GABA A} receptor is reduced in the hippocampus (see International Patent Publication WO2007 / 019312). Such results suggest that α5 upregulation of the function of containing GABA A _R is, it may be effective in the treatment of cognitive disorders associated with the CNS disorder.
Therefore, positive allosteric modulators useful α5 containing GABA A _R in the therapeutic preparations for the treatment of cognitive disorders associated with the CNS disorder is required.

International Publication No. 2007/01/9312

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせであって、式Ｉにおいて：
Ｕと、αおよびβによって表される２個の炭素原子とが一緒になって、０個〜２個の窒素原子を有する５員または６員の芳香環を形成し；
Ａは、Ｃ、ＣＲ ^６ 、またはＮであり；
ＢおよびＦは各々独立して、Ｃ、ＣＲ ^６ 、およびＮから選択され、ここでＢとＦとの両方がＮであることはできず；
Ｄは、Ｎ、ＮＲ ^７ 、Ｏ、ＣＲ ^６ またはＣ（Ｒ ^６ ） _２ であり；
Ｅは、Ｎ、ＮＲ ^７ 、ＣＲ ^６ またはＣ（Ｒ ^６ ） _２ であり；
Ｗは、Ｎ、ＮＲ ^７ 、ＣＲ ^６ またはＣ（Ｒ ^６ ） _２ であり；
Ｘは、Ｎ、ＮＲ ^７ 、Ｏ、ＣＲ ^６ またはＣ（Ｒ ^６ ） _２ であり；
ＹおよびＺは各々独立して、Ｃ、ＣＲ ^６ 、およびＮから選択され、ここでＹとＺとの両方がＮであることはできず；
Ｖは、ＣまたはＣＲ ^６ であるか、
あるいはＺがＣまたはＣＲ ^６ である場合、Ｖは、Ｃ、ＣＲ ^６ 、またはＮであり；
ここでＸ、Ｙ、Ｚ、ＶおよびＷによって形成される環が

である場合、Ｒ ^２ は、−ＯＲ ^８ 、−ＳＲ ^８ 、−（ＣＨ _２ ） _ｎ ＯＲ ^８ 、−（ＣＨ _２ ） _ｎ Ｏ（ＣＨ _２ ） _ｎ Ｒ ^８ 、−（ＣＨ _２ ） _ｐ Ｒ ^８ および−（ＣＨ _２ ） _ｎ Ｎ（Ｒ’’）Ｒ ^１０ であり；ここでＲ ^２ は独立して、０個〜５個のＲ’で置換されており；
ｍおよびｎは独立して、０〜４から選択される整数であり；
ｐは、２〜４から選択される整数であり；
結合

の各存在は、単結合または二重結合のいずれかであり；
Ｒ ^１ 、Ｒ ^２ 、Ｒ ^４ 、およびＲ ^５ の各存在は、各々独立して：
ハロゲン、−Ｒ、−ＯＲ、−ＮＯ _２ 、−ＮＣＳ、−ＣＮ、−ＣＦ _３ 、−ＯＣＦ _３ 、−ＳｉＲ _３ 、−Ｎ（Ｒ） _２ 、−ＳＲ、−ＳＯＲ、−ＳＯ _２ Ｒ、−ＳＯ _２ Ｎ（Ｒ） _２ 、−ＳＯ _３ Ｒ、−（ＣＲ _２ ） _１〜３ Ｒ、−（ＣＲ _２ ） _１〜３ −ＯＲ、−（ＣＲ _２ ） _０〜３ −Ｃ（Ｏ）ＮＲ（ＣＲ _２ ） _０〜３ Ｒ、−（ＣＲ _２ ） _０〜３ −Ｃ（Ｏ）ＮＲ（ＣＲ _２ ） _０〜３ ＯＲ、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＣＨ _２ Ｃ（Ｏ）Ｒ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｎ（Ｒ） _２ 、−ＯＣ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｎ（Ｒ） _２ 、−ＯＣ（Ｏ）Ｎ（Ｒ） _２ 、−Ｃ（Ｓ）Ｎ（Ｒ） _２ 、−（ＣＲ _２ ） _０〜３ ＮＨＣ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＮ（Ｒ） _２ 、−Ｎ（Ｒ）ＳＯ _２ Ｒ、−Ｎ（Ｒ）ＳＯ _２ Ｎ（Ｒ） _２ 、−Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｓ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ） _２ 、−Ｎ（Ｒ）Ｃ（Ｓ）Ｎ（Ｒ） _２ 、−Ｎ（ＣＯＲ）ＣＯＲ、−Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＨ）Ｎ（Ｒ） _２ 、−Ｃ（Ｏ）Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＯＲ）Ｒ、−ＯＰ（Ｏ）（ＯＲ） _２ 、−Ｐ（Ｏ）（Ｒ） _２ 、−Ｐ（Ｏ）（ＯＲ） _２ 、および−Ｐ（Ｏ）（Ｈ）（ＯＲ）から選択され；
Ｒ ^３ は、存在しないか、または：
ハロゲン、−Ｒ、−ＯＲ、−ＮＯ _２ 、−ＮＣＳ、−ＣＮ、−ＣＦ _３ 、−ＯＣＦ _３ 、−ＳｉＲ _３ 、−Ｎ（Ｒ） _２ 、−ＳＲ、−ＳＯＲ、−ＳＯ _２ Ｒ、−ＳＯ _２ Ｎ（Ｒ） _２ 、−ＳＯ _３ Ｒ、−（ＣＲ _２ ） _１〜３ Ｒ、−（ＣＲ _２ ） _１〜３ −ＯＲ、−（ＣＲ _２ ） _０〜３ −Ｃ（Ｏ）ＮＲ（ＣＲ _２ ） _０〜３ Ｒ、−（ＣＲ _２ ） _０〜３ −Ｃ（Ｏ）ＮＲ（ＣＲ _２ ） _０〜３ ＯＲ、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＣＨ _２ Ｃ（Ｏ）Ｒ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｎ（Ｒ） _２ 、−ＯＣ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｎ（Ｒ） _２ 、−ＯＣ（Ｏ）Ｎ（Ｒ） _２ 、−Ｃ（Ｓ）Ｎ（Ｒ） _２ 、−（ＣＲ _２ ） _０〜３ ＮＨＣ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＮ（Ｒ） _２ 、−Ｎ（Ｒ）ＳＯ _２ Ｒ、−Ｎ（Ｒ）ＳＯ _２ Ｎ（Ｒ） _２ 、−Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｓ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ） _２ 、−Ｎ（Ｒ）Ｃ（Ｓ）Ｎ（Ｒ） _２ 、−Ｎ（ＣＯＲ）ＣＯＲ、−Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＨ）Ｎ（Ｒ） _２ 、−Ｃ（Ｏ）Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＯＲ）Ｒ、−ＯＰ（Ｏ）（ＯＲ） _２ 、−Ｐ（Ｏ）（Ｒ） _２ 、−Ｐ（Ｏ）（ＯＲ） _２ 、および−Ｐ（Ｏ）（Ｈ）（ＯＲ）から選択され；
各Ｒ ^６ は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
各Ｒ ^７ は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
各Ｒ ^８ は独立して、−（Ｃ１〜Ｃ６）アルキル、−（Ｃ３〜Ｃ１０）−シクロアルキル、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ ^８ の各存在は独立して、０個〜５個のＲ’で置換されており；
各Ｒ ^１０ は独立して、−（Ｃ３〜Ｃ１０）−シクロアルキル、３員〜１０員のヘテロシクリル−、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ ^１０ の各存在は独立して、０個〜５個のＲ’で置換されており；
各Ｒは独立して：
Ｈ−、
（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ３〜Ｃ１０）−シクロアルキル−、
（Ｃ３〜Ｃ１０）−シクロアルケニル−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−、
（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
３員〜１０員のヘテロシクリル−、
（３員〜１０員のヘテロシクリル）−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
５員〜１０員のヘテロアリール−、
（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ１２）−脂肪族−、
（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−；および
（５員〜１０員のヘテロアリール）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）−脂肪族−
から選択され；
ここで該ヘテロシクリルは、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ _２ から独立して選択される１個〜４個のヘテロ原子を有し、そして該ヘテロアリールは、Ｎ、ＮＨ、Ｏ、およびＳから独立して選択される１個〜４個のヘテロ原子を有し；
ここでＲの各存在は独立して、０個〜５個のＲ’で置換されているか；
あるいは２個のＲ基が同じ原子に結合している場合、該２個のＲ基は、これらが結合している原子と一緒になって、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ _２ から独立して選択される０個〜４個のヘテロ原子を有する３員〜１０員の芳香族または非芳香族の環を形成し得、ここで該環は、０個〜５個のＲ’で必要に応じて置換されており、そして該環は、（Ｃ６〜Ｃ１０）アリール、５員〜１０員のヘテロアリール、（Ｃ３〜Ｃ１０）シクロアルキル、または３員〜１０員のヘテロシクリルに必要に応じて縮合しており；
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ _２ ＯＲ’’、−ＣＨ _２ ＮＲ’’ _２ 、−Ｃ（Ｏ）Ｎ（Ｒ’’） _２ 、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ _２ 、−ＮＣＳ、−ＣＮ、−ＣＦ _３ 、−ＯＣＦ _３ および−Ｎ（Ｒ’’） _２ から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、−（Ｃ１〜Ｃ６）−脂肪族、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択され、ここでＲ’’の各存在は、ハロゲン、−Ｒ ^ｏ 、−ＯＲ ^ｏ 、オキソ、−ＣＨ _２ ＯＲ ^ｏ 、−ＣＨ _２ Ｎ（Ｒ ^ｏ ） _２ 、−Ｃ（Ｏ）Ｎ（Ｒ ^ｏ ） _２ 、−Ｃ（Ｏ）ＯＲ ^ｏ 、−ＮＯ _２ 、−ＮＣＳ、−ＣＮ、−ＣＦ _３ 、−ＯＣＦ _３ および−Ｎ（Ｒ ^ｏ ） _２ から選択される０個〜３個の置換基で独立して置換されており、ここでＲ ^ｏ の各存在は独立して、−（Ｃ１〜Ｃ６）−脂肪族、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、および（Ｃ６〜Ｃ１０）−アリール−から選択される、
化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせ。
（項目２）
式ＩＩ：

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせであって、式ＩＩにおいて：
ｍは、０〜３であり；
各Ｒ ^１ は独立して、ハロゲン、−Ｈ、−（Ｃ１〜Ｃ６）アルキル、−ＯＨ、−Ｏ（（Ｃ１〜Ｃ６）アルキル）、−ＮＯ _２ 、−ＣＮ、−ＣＦ _３ 、および−ＯＣＦ _３ から選択され、ここでＲ ^１ は独立して、０個〜５個のＲ’で置換されており；
Ｒ ^２ は：
−Ｈ、ハロゲン、−（Ｃ１〜Ｃ６）アルキル、−ＯＨ、−Ｏ（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）Ｏ（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）ＮＲ _２ 、
（Ｃ６〜Ｃ１０）−アリール−、
（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ１２）脂肪族−、
（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（５員〜１０員のヘテロアリール）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、および
（３員〜１０員のヘテロシクリル）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−
から選択され、
ここでＲ ^２ は独立して、０個〜５個のＲ’で置換されており；
Ｒ ^３ は：
−（Ｃ１〜Ｃ６）アルキル、−（Ｃ２〜Ｃ６）アルケニル、−Ｃ≡ＣＨ、−ＣＮ、ハロゲン、−ＳＯ _２ （（Ｃ６〜Ｃ１０）−アリール）、−ＳＯ _２（ （Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）Ｎ（（Ｃ１〜Ｃ６）アルキル） _２ 、−Ｃ（Ｏ）ＮＨ _２ 、−Ｃ（Ｏ）Ｏ（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）（（Ｃ１〜Ｃ６）アルキル）、−（Ｃ６〜Ｃ１０）アリール、５員〜１０員のヘテロアリール、５員〜１０員のヘテロシクリルから選択され、ここでＲ ^３ は独立して、０個〜５個のＲ’で置換されており；
Ｒ ^４ およびＲ ^５ は各々独立して、−Ｈ、ハロゲンおよび−（Ｃ１〜Ｃ６）アルキルから選択され；
Ｒ ^６ は、−Ｈおよび−（Ｃ１〜Ｃ６）アルキルから選択され；
各Ｒは独立して：
Ｈ−、
（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ３〜Ｃ１０）−シクロアルキル−、
（Ｃ３〜Ｃ１０）−シクロアルケニル−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−、
（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
３員〜１０員のヘテロシクリル−、
（３員〜１０員のヘテロシクリル）−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
５員〜１０員のヘテロアリール−、
（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ１２）−脂肪族−、
（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−；および
（５員〜１０員のヘテロアリール）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）−脂肪族−
から選択され；
ここで該ヘテロシクリルは、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ _２ から独立して選択される１個〜４個のヘテロ原子を有し、そして該ヘテロアリールは、Ｎ、ＮＨ、Ｏ、およびＳから独立して選択される１個〜４個のヘテロ原子を有し；
ここでＲの各存在は独立して、０個〜５個のＲ’で置換されているか；
あるいは２個のＲ基が同じ原子に結合している場合、該２個のＲ基は、これらが結合している原子と一緒になって、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ _２ から独立して選択される０個〜４個のヘテロ原子を有する３員〜１０員の芳香族または非芳香族の環を形成し得、ここで該環は、０個〜５個のＲ’で必要に応じて置換されており、そして該環は、（Ｃ６〜Ｃ１０）アリール、５員〜１０員のヘテロアリール、（Ｃ３〜Ｃ１０）シクロアルキル、または３員〜１０員のヘテロシクリルに必要に応じて縮合しており；
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ _２ ＯＲ’’、−ＣＨ _２ ＮＲ’’ _２ 、−Ｃ（Ｏ）Ｎ（Ｒ’’） _２ 、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ _２ 、−ＮＣＳ、−ＣＮ、−ＣＦ _３ 、−ＯＣＦ _３ および−Ｎ（Ｒ’’） _２ から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択される、
化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせ。
（項目３）
式ＩＶ：

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせであって、式ＩＶにおいて：
ｍは、０〜３であり；
各Ｒ ^１ は独立して、ハロゲン、−Ｈ、−（Ｃ１〜Ｃ６）アルキル、−Ｃ≡ＣＨ、−ＯＨ、−Ｏ（（Ｃ１〜Ｃ６）アルキル）、−ＮＯ _２ 、−ＣＮ、−ＣＦ _３ 、−ＯＣＦ _３ から選択され、ここでＲ ^１ は独立して、０個〜５個のＲ’で置換されており；
Ｒ ^２ は、−ＯＲ ^８ 、−ＳＲ ^８ 、−（ＣＨ _２ ） _ｎ ＯＲ ^８ 、−（ＣＨ _２ ） _ｎ Ｏ（ＣＨ _２ ） _ｎ Ｒ ^８ 、−（ＣＨ _２ ） _ｐ Ｒ ^８ および−（ＣＨ _２ ） _ｎ Ｎ（Ｒ’’）Ｒ ^１０ から選択され、ここでｎは、０〜４から選択される整数であり；ｐは、２〜４から選択される整数であり；各Ｒ ^８ は独立して、−（Ｃ１〜Ｃ６）アルキル、−（Ｃ３〜Ｃ１０）−シクロアルキル、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ ^８ の各存在は独立して、０個〜５個のＲ’で置換されており；各Ｒ ^１０ は独立して、−（Ｃ３〜Ｃ１０）−シクロアルキル、３員〜１０員のヘテロシクリル−、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ ^１０ の各存在は独立して、０個〜５個のＲ’で置換されており；ここでＲ ^２ は独立して、０個〜５個のＲ’で置換されており；
Ｒ ^３ は：
−Ｈ、−ＣＮ、ハロゲン（例えば、Ｂｒ）、−（Ｃ１〜Ｃ６）アルキル、−Ｃ≡ＣＨ、−ＳＯ _２（ （Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）Ｎ（（Ｃ１〜Ｃ６）アルキル） _２ 、）、−Ｃ（Ｏ）ＮＨ（（Ｃ１〜Ｃ６）脂肪族） _２ 、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、−Ｃ（Ｏ）（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）Ｏ（（Ｃ１〜Ｃ６）アルキル）、５員または６員のヘテロシクリル、および５員または６員のヘテロアリールから選択され；ここでＲ ^３ は独立して、０個〜５個のＲ’で置換されており；
Ｒ ^４ およびＲ ^５ は各々独立して、−Ｈ、ハロゲンおよび−（Ｃ１〜Ｃ６）アルキルから選択され；
Ｒ ^６ は、−Ｈおよび−（Ｃ１〜Ｃ６）アルキルから選択され；
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ _２ ＯＲ’’、−ＣＨ _２ ＮＲ’’ _２ 、−Ｃ（Ｏ）Ｎ（Ｒ’’） _２ 、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ _２ 、−ＮＣＳ、−ＣＮ、−ＣＦ _３ 、−ＯＣＦ _３ および−Ｎ（Ｒ’’） _２ から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択される、
化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせ。
（項目４）

から選択される化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせ。
（項目５）

から選択される化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせ。
（項目６）
治療有効量の項目１〜５のいずれか１項に記載の化合物もしくはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体または組み合わせ；および受容可能なキャリア、アジュバントまたはビヒクルを含む薬学的組成物。
（項目７）
前記組成物が、第２の治療剤をさらに含む、項目６に記載の薬学的組成物。
（項目８）
前記第２の治療剤が、抗精神病薬、メマンチンおよびアセチルコリンエステラーゼ阻害剤（ＡＣｈＥ−Ｉ）から選択される、項目７に記載の薬学的組成物。
（項目９）
前記第２の治療剤が、アリピプラゾール、オランザピンおよびジプラシドンならびにそれらの薬学的に受容可能な塩、水和物、溶媒和物および多形から選択される抗精神病薬である、項目７に記載の薬学的組成物。
（項目１０）
前記第２の治療剤が、メマンチン、その薬学的に受容可能な塩、水和物、溶媒和物または多形である、項目７に記載の薬学的組成物。
（項目１１）
前記第２の治療剤が、ドネペジル、ガランタミンおよびリバスチグミンならびにそれらの薬学的に受容可能な塩、水和物、溶媒和物および多形から選択されるＡＣｈＥ−Ｉである、項目７に記載の薬学的組成物。
（項目１２）
中枢神経系（ＣＮＳ）障害に関連する認知障害の処置を必要とする被験体におけるＣＮＳ障害に関連する認知障害を処置する方法であって、項目１〜５のいずれか１項に記載の化合物または項目６〜１１のいずれか１項に記載の薬学的組成物を投与する工程を含む、方法。
（項目１３）
前記ＣＮＳ障害が、加齢性認知障害である、項目１２に記載の方法。
（項目１４）
前記加齢性認知障害が、軽度認知障害（ＭＣＩ）である、項目１３に記載の方法。
（項目１５）
前記軽度認知障害が、健忘性軽度認知障害（ＡＭＣＩ）である、項目１４に記載の方法。
（項目１６）
前記ＣＮＳ障害が、認知症である、項目１２に記載の方法。
（項目１７）
前記認知症が、アルツハイマー病である、項目１６に記載の方法。
（項目１８）
前記ＣＮＳ障害が、統合失調症または双極性障害である、項目１２に記載の方法。
（項目１９）
前記ＣＮＳ障害が、筋萎縮性側索硬化症（ＡＬＳ）である、項目１２に記載の方法。
（項目２０）
前記ＣＮＳ障害が、外傷後ストレス障害（ＰＴＳＤ）である、項目１２に記載の方法。
（項目２１）
前記ＣＮＳ障害が、がん治療に関連する、項目１２に記載の方法。
（項目２２）
前記ＣＮＳ障害が、精神遅滞である、項目１２に記載の方法。
（項目２３）
前記ＣＮＳ障害が、パーキンソン病（ＰＤ）である、項目１２に記載の方法。
（項目２４）
前記ＣＮＳ障害が、自閉症である、項目１２に記載の方法。
（項目２５）
前記ＣＮＳ障害が、強迫行動である、項目１２に記載の方法。
（項目２６）
前記ＣＮＳ障害が、物質嗜癖である、項目１２に記載の方法。
（項目２７）
医薬として使用するための、項目１〜５のいずれか１項に記載の化合物。
（項目２８）
中枢神経系（ＣＮＳ）障害に関連する認知障害の処置を必要とする被験体におけるＣＮＳ障害に関連する認知障害を処置するのに使用するための、項目１〜５のいずれか１項に記載の化合物。
（項目２９）
前記ＣＮＳ障害が、加齢性認知障害である、項目２８に記載の使用するための化合物。
（項目３０）
前記加齢性認知障害が、軽度認知障害（ＭＣＩ）である、項目２９に記載の使用するための化合物。
（項目３１）
前記軽度認知障害が、健忘性軽度認知障害（ＡＭＣＩ）である、項目３０に記載の使用するための化合物。
（項目３２）
前記ＣＮＳ障害が、認知症である、項目２８に記載の使用するための化合物。
（項目３３）
前記認知症が、アルツハイマー病である、項目３２に記載の化合物。
（項目３４）
前記ＣＮＳ障害が、統合失調症または双極性障害である、項目２８に記載の使用するための化合物。
（項目３５）
前記ＣＮＳ障害が、筋萎縮性側索硬化症（ＡＬＳ）である、項目２８に記載の使用するための化合物。
（項目３６）
前記ＣＮＳ障害が、外傷後ストレス障害（ＰＴＳＤ）である、項目２８に記載の使用するための化合物。
（項目３７）
前記ＣＮＳ障害が、がん治療に関連する、項目２８に記載の使用するための化合物。
（項目３８）
前記ＣＮＳ障害が、精神遅滞である、項目２８に記載の使用するための化合物。
（項目３９）
前記ＣＮＳ障害が、パーキンソン病（ＰＤ）である、項目２８に記載の使用するための化合物。
（項目４０）
前記ＣＮＳ障害が、自閉症である、項目２８に記載の使用するための化合物。
（項目４１）
前記ＣＮＳ障害が、強迫行動である、項目２８に記載の使用するための化合物。
（項目４２）
前記ＣＮＳ障害が、物質嗜癖である、項目２８に記載の使用するための化合物。
（項目４３）
中枢神経系（ＣＮＳ）障害に関連する認知障害の処置を必要とする被験体におけるＣＮＳ障害に関連する認知障害を処置するための医薬の調製における、項目１〜５のいずれか１項に記載の化合物または項目６〜１１のいずれか１項に記載の薬学的組成物の使用。
（項目４４）
前記ＣＮＳ障害が、加齢性認知障害である、項目４３に記載の使用。
（項目４５）
前記加齢性認知障害が、軽度認知障害（ＭＣＩ）である、項目４４に記載の使用。
（項目４６）
前記軽度認知障害が、健忘性軽度認知障害（ＡＭＣＩ）である、項目４５に記載の使用。
（項目４７）
前記ＣＮＳ障害が、認知症である、項目４３に記載の使用。
（項目４８）
前記認知症が、アルツハイマー病である、項目４７に記載の使用。
（項目４９）
前記ＣＮＳ障害が、統合失調症または双極性障害である、項目４３に記載の使用。
（項目５０）
前記ＣＮＳ障害が、筋萎縮性側索硬化症（ＡＬＳ）である、項目４３に記載の使用。
（項目５１）
前記ＣＮＳ障害が、外傷後ストレス障害（ＰＴＳＤ）である、項目４３に記載の使用。
（項目５２）
前記ＣＮＳ障害が、がん治療に関連する、項目４３に記載の使用。
（項目５３）
前記ＣＮＳ障害が、精神遅滞である、項目４３に記載の使用。
（項目５４）
前記ＣＮＳ障害が、パーキンソン病（ＰＤ）である、項目４３に記載の使用。
（項目５５）
前記ＣＮＳ障害が、自閉症である、項目４３に記載の使用。
（項目５６）
前記ＣＮＳ障害が、強迫行動である、項目４３に記載の使用。
（項目５７）
前記ＣＮＳ障害が、物質嗜癖である、項目４３に記載の使用。
発明の要旨
本発明は、式Ｉ：

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供することによって、上記必要性に取り組む。式Ｉにおいて：
Ｕと、αおよびβによって表される２個の炭素原子とが一緒になって、０個〜２個の窒素原子を有する５員または６員の芳香環を形成し；
Ａは、Ｃ、ＣＲ^６、またはＮであり；
ＢおよびＦは各々独立して、Ｃ、ＣＲ^６、およびＮから選択され、ここでＢとＦとの両方がＮであることはできず；
Ｄは、Ｎ、ＮＲ^７、Ｏ、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｅは、Ｎ、ＮＲ^７、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｗは、Ｎ、ＮＲ^７、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｘは、Ｎ、ＮＲ^７、Ｏ、ＣＲ^６またはＣ（Ｒ^６）_２であり；
ＹおよびＺは各々独立して、Ｃ、ＣＲ^６、およびＮから選択され、ここでＹとＺとの両方がＮであることはできず；
Ｖは、ＣまたはＣＲ^６であるか、
あるいはＺがＣまたはＣＲ^６である場合、Ｖは、Ｃ、ＣＲ^６、またはＮであり；
ここでＸ、Ｙ、Ｚ、ＶおよびＷによって形成される環が

である場合、Ｒ^２は、−ＯＲ^８、−ＳＲ^８、−（ＣＨ_２）_ｎＯＲ^８、−（ＣＨ_２）_ｎＯ（ＣＨ_２）_ｎＲ^８、−（ＣＨ_２）_ｐＲ^８および−（ＣＨ_２）_ｎＮ（Ｒ’’）Ｒ^１０であり；ここでＲ^２は独立して、０個〜５個のＲ’で置換されており；
ｍおよびｎは独立して、０〜４から選択される整数であり；
ｐは、２〜４から選択される整数であり；
結合

の各存在は、単結合または二重結合のいずれかであり；
Ｒ^１、Ｒ^２、Ｒ^４、およびＲ^５の各存在は、各々独立して：
ハロゲン、−Ｒ、−ＯＲ、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３、−ＳｉＲ_３、−Ｎ（Ｒ）_２、−ＳＲ、−ＳＯＲ、−ＳＯ_２Ｒ、−ＳＯ_２Ｎ（Ｒ）_２、−ＳＯ_３Ｒ、−（ＣＲ_２）_１〜３Ｒ、−（ＣＲ_２）_１〜３−ＯＲ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３Ｒ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３ＯＲ、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＣＨ_２Ｃ（Ｏ）Ｒ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｎ（Ｒ）_２、−Ｃ（Ｓ）Ｎ（Ｒ）_２、−（ＣＲ_２）_０〜３ＮＨＣ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＮ（Ｒ）_２、−Ｎ（Ｒ）ＳＯ_２Ｒ、−Ｎ（Ｒ）ＳＯ_２Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｓ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｓ）Ｎ（Ｒ）_２、−Ｎ（ＣＯＲ）ＣＯＲ、−Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＨ）Ｎ（Ｒ）_２、−Ｃ（Ｏ）Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＯＲ）Ｒ、−ＯＰ（Ｏ）（ＯＲ）_２、−Ｐ（Ｏ）（Ｒ）_２、−Ｐ（Ｏ）（ＯＲ）_２、および−Ｐ（Ｏ）（Ｈ）（ＯＲ）
から選択され；
Ｒ^３は、存在しないか、または：
ハロゲン、−Ｒ、−ＯＲ、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３、−ＳｉＲ_３、−Ｎ（Ｒ）_２、−ＳＲ、−ＳＯＲ、−ＳＯ_２Ｒ、−ＳＯ_２Ｎ（Ｒ）_２、−ＳＯ_３Ｒ、−（ＣＲ_２）_１〜３Ｒ、−（ＣＲ_２）_１〜３−ＯＲ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３Ｒ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３ＯＲ、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＣＨ_２Ｃ（Ｏ）Ｒ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｎ（Ｒ）_２、−Ｃ（Ｓ）Ｎ（Ｒ）_２、−（ＣＲ_２）_０〜３ＮＨＣ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＮ（Ｒ）_２、−Ｎ（Ｒ）ＳＯ_２Ｒ、−Ｎ（Ｒ）ＳＯ_２Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｓ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｓ）Ｎ（Ｒ）_２、−Ｎ（ＣＯＲ）ＣＯＲ、−Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＨ）Ｎ（Ｒ）_２、−Ｃ（Ｏ）Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＯＲ）Ｒ、−ＯＰ（Ｏ）（ＯＲ）_２、−Ｐ（Ｏ）（Ｒ）_２、−Ｐ（Ｏ）（ＯＲ）_２、および−Ｐ（Ｏ）（Ｈ）（ＯＲ）
から選択され；
各Ｒ^６は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
各Ｒ^７は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
各Ｒ^８は独立して、−（Ｃ１〜Ｃ６）アルキル、−（Ｃ３〜Ｃ１０）−シクロアルキル、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ^８の各存在は独立して、０個〜５個のＲ’で置換されており；
各Ｒ^１０は独立して、−（Ｃ３〜Ｃ１０）−シクロアルキル、３員〜１０員のヘテロシクリル−、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ^１０の各存在は独立して、０個〜５個のＲ’で置換されており；
各Ｒは独立して：
Ｈ−、
（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ３〜Ｃ１０）−シクロアルキル−、
（Ｃ３〜Ｃ１０）−シクロアルケニル−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−、
（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
３員〜１０員のヘテロシクリル−、
（３員〜１０員のヘテロシクリル）−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
５員〜１０員のヘテロアリール−、
（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ１２）−脂肪族−、
（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−；および
（５員〜１０員のヘテロアリール）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）−脂肪族−
から選択され；
ここでこのヘテロシクリルは、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される１個〜４個のヘテロ原子を有し、そしてこのヘテロアリールは、Ｎ、ＮＨ、Ｏ、およびＳから独立して選択される１個〜４個のヘテロ原子を有し；
ここでＲの各存在は独立して、０個〜５個のＲ’で置換されているか；
あるいは２個のＲ基が同じ原子に結合している場合、これらの２個のＲ基は、これらが結合している原子と一緒になって、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される０個〜４個のヘテロ原子を有する３員〜１０員の芳香族または非芳香族の環を形成し得、ここでこの環は、０個〜５個のＲ’で必要に応じて置換されており、そしてこの環は、（Ｃ６〜Ｃ１０）アリール、５員〜１０員のヘテロアリール、（Ｃ３〜Ｃ１０）シクロアルキル、または３員〜１０員のヘテロシクリルに必要に応じて縮合しており；
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ_２ＯＲ’’、−ＣＨ_２ＮＲ’’_２、−Ｃ（Ｏ）Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ’’）_２から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、−（Ｃ１〜Ｃ６）−脂肪族、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択され、ここでＲ’’の各存在は、ハロゲン、−Ｒ^ｏ、−ＯＲ^ｏ、オキソ、−ＣＨ_２ＯＲ^ｏ、−ＣＨ_２ＮＲ^ｏ _２、−Ｃ（Ｏ）Ｎ（Ｒ^ｏ）_２、−Ｃ（Ｏ）ＯＲ^ｏ、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ^ｏ）_２から選択される０個〜３個の置換基で独立して置換されており、ここでＲ^ｏの各存在は独立して、−（Ｃ１〜Ｃ６）−脂肪族、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、および（Ｃ６〜Ｃ１０）−アリール−から選択される。 The present invention provides, for example:
(Item 1)
Formula I:

Compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, in formula I:
U and the two carbon atoms represented by α and β together form a 5- or 6-membered aromatic ring with 0 to 2 nitrogen atoms;
A is C, CR ⁶ , Or N;
B and F are independent of C and CR, respectively. ⁶ , And N, where both B and F cannot be N;
D is N, NR ⁷ , O, CR ⁶ Or C (R ⁶ ) ₂ And;
E is N, NR ⁷ , CR ⁶ Or C (R ⁶ ) ₂ And;
W is N, NR ⁷ , CR ⁶ Or C (R ⁶ ) ₂ And;
X is N, NR ⁷ , O, CR ⁶ Or C (R ⁶ ) ₂ And;
Y and Z are independent of C and CR, respectively. ⁶ , And N, where both Y and Z cannot be N;
V is C or CR ⁶ Is it?
Or Z is C or CR ⁶ If, V is C, CR ⁶ , Or N;
Here the ring formed by X, Y, Z, V and W

If, then R ² Is -OR ⁸ , -SR ⁸ ,-(CH ₂ ) _n OR ⁸ ,-(CH ₂ ) _n O (CH ₂ ) _n R ⁸ ,-(CH ₂ ) _p R ⁸ And-(CH ₂ ) _n N (R'') R ¹⁰ And here R ² Are independently replaced by 0-5 R';
m and n are integers independently selected from 0 to 4;
p is an integer selected from 2-4;
Join

Each presence of is either a single bond or a double bond;
R ¹ , R ² , R ⁴ , And R ⁵ Each being is independent of:
Halogen, -R, -OR, -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ , -SiR ₃ , -N (R) ₂ , -SR, -SOR, -SO ₂ R, -SO ₂ N (R) ₂ , -SO ₃ R,-(CR ₂ ) _1-3 R,-(CR ₂ ) _1-3 -OR,-(CR ₂ ) _0-3 -C (O) NR (CR) ₂ ) _0-3 R,-(CR ₂ ) _0-3 -C (O) NR (CR) ₂ ) _0-3 OR, -C (O) R, -C (O) C (O) R, -C (O) CH ₂ C (O) R, -C (S) R, -C (S) OR, -C (O) OR, -C (O) C (O) OR, -C (O) C (O) N (R) ) ₂ , -OC (O) R, -C (O) N (R) ₂ , -OC (O) N (R) ₂ , -C (S) N (R) ₂ ,-(CR ₂ ) _0-3 NHC (O) R, -N (R) N (R) COR, -N (R) N (R) C (O) OR, -N (R) N (R) CON (R) ₂ , -N (R) SO ₂ R, -N (R) SO ₂ N (R) ₂ , -N (R) C (O) OR, -N (R) C (O) R, -N (R) C (S) R, -N (R) C (O) N (R) ₂ , -N (R) C (S) N (R) ₂ , -N (COR) COR, -N (OR) R, -C (= NH) N (R) ₂ , -C (O) N (OR) R, -C (= NOR) R, -OP (O) (OR) ₂ , -P (O) (R) ₂ , -P (O) (OR) ₂ , And -P (O) (H) (OR);
R ³ Does not exist or:
Halogen, -R, -OR, -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ , -SiR ₃ , -N (R) ₂ , -SR, -SOR, -SO ₂ R, -SO ₂ N (R) ₂ , -SO ₃ R,-(CR ₂ ) _1-3 R,-(CR ₂ ) _1-3 -OR,-(CR ₂ ) _0-3 -C (O) NR (CR) ₂ ) _0-3 R,-(CR ₂ ) _0-3 -C (O) NR (CR) ₂ ) _0-3 OR, -C (O) R, -C (O) C (O) R, -C (O) CH ₂ C (O) R, -C (S) R, -C (S) OR, -C (O) OR, -C (O) C (O) OR, -C (O) C (O) N (R) ) ₂ , -OC (O) R, -C (O) N (R) ₂ , -OC (O) N (R) ₂ , -C (S) N (R) ₂ ,-(CR ₂ ) _0-3 NHC (O) R, -N (R) N (R) COR, -N (R) N (R) C (O) OR, -N (R) N (R) CON (R) ₂ , -N (R) SO ₂ R, -N (R) SO ₂ N (R) ₂ , -N (R) C (O) OR, -N (R) C (O) R, -N (R) C (S) R, -N (R) C (O) N (R) ₂ , -N (R) C (S) N (R) ₂ , -N (COR) COR, -N (OR) R, -C (= NH) N (R) ₂ , -C (O) N (OR) R, -C (= NOR) R, -OP (O) (OR) ₂ , -P (O) (R) ₂ , -P (O) (OR) ₂ , And -P (O) (H) (OR);
Each R ⁶ Are independently -H or-(C1-C6) alkyl;
Each R ⁷ Are independently -H or-(C1-C6) alkyl;
Each R ⁸ Are independently -(C1-C6) alkyl,-(C3-C10) -cycloalkyl, (C6-C10) -aryl, or 5- to 10-membered heteroaryl, where R ⁸ Each existence of is independently replaced by 0-5 R';
Each R ¹⁰ Are independently-(C3-C10) -cycloalkyl, 3-member to 10-membered heterocyclyl-, (C6-C10) -aryl, or 5- to 10-membered heteroaryl, where R ¹⁰ Each existence of is independently replaced by 0-5 R';
Each R is independent:
H-,
(C1-C12) -aliphatic-,
(C3 to C10) -Cycloalkyl-,
(C3 to C10) -Cycloalkenyl-,
[(C3 to C10) -cycloalkyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkyl] -O- (C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl] -O- (C1 to C12) -aliphatic-,
(C6 to C10) -aryl-,
(C6 to C10) -aryl- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-O- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-N (R'')-(C1 to C12) aliphatic-,
Heterocyclyl of 3 to 10 members-,
(3-10 member heterocyclyl)-(C1-C12) Aliphatic-,
(3-10 member heterocyclyl) -O- (C1-C12) aliphatic-,
(3-10 member heterocyclyl) -N (R'')-(C1-C12) aliphatic-,
5-10 member heteroaryl-,
(5- to 10-membered heteroaryl)-(C1-C12) -aliphatic-,
(5- to 10-membered heteroaryl) -O- (C1-C12) -aliphatic-; and
(5- to 10-membered heteroaryl) -N (R'')-(C1-C12) -aliphatic-
Selected from;
Here, the heterocyclyl is N, NH, O, S, SO, and SO. ₂ Has 1 to 4 heteroatoms independently selected from, and the heteroaryl has 1 to 4 heteroatoms independently selected from N, NH, O, and S. death;
Where each existence of R is independently replaced by 0-5 R';
Alternatively, if two R groups are attached to the same atom, the two R groups together with the atom to which they are attached are N, NH, O, S, SO, and SO. ₂ Can form a 3- to 10-membered aromatic or non-aromatic ring with 0-4 heteroatoms independently selected from, where the ring is 0-5 R'. The ring is optionally substituted with, and the ring is required for (C6-C10) aryl, 5-membered to 10-membered heteroaryl, (C3-C10) cycloalkyl, or 3-membered to 10-membered heterocyclyl. Condensed accordingly;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, and -CH. ₂ OR'', -CH ₂ NR'''' ₂ , -C (O) N (R'') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ And -N (R'') ₂ Selected from;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl,-(C1-C6) -aliphatic, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl. 5, 10-membered heteroaryl-, (C6-C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1) ~ C6) -alkyl-, (5- to 10-membered heteroaryl) -O- (C1-C6) -alkyl-, and (C6-C10) -aryl-O- (C1-C6) -alkyl- And here each presence of R'' is halogen, -R ^o , -OR ^o , Oxo, -CH ₂ OR ^o , -CH ₂ N (R) ^o ) ₂ , -C (O) N (R) ^o ) ₂ , -C (O) OR ^o , -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ And -N (R ^o ) ₂ It is independently substituted with 0 to 3 substituents selected from, where R ^o Independently, each presence of-(C1-C6) -aliphatic, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-, and (C6-C10). ) -Aryl-selected from
A compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.
(Item 2)
Equation II:

Compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, in Formula II:
m is 0 to 3;
Each R ¹ Halogen, -H,-(C1-C6) alkyl, -OH, -O ((C1-C6) alkyl), -NO independently ₂ , -CN, -CF ₃ , And -OCF ₃ Selected from, here R ¹ Are independently replaced by 0-5 R';
R ² teeth:
-H, Halogen,-(C1-C6) alkyl, -OH, -O ((C1-C6) alkyl), -C (O) O ((C1-C6) alkyl), -C (O) NR ₂ ,
(C6 to C10) -aryl-,
(C6 to C10) -aryl- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-O- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-N (R'')-(C1 to C12) aliphatic-,
(5- to 10-membered heteroaryl)-(C1-C12) aliphatic-,
(5- to 10-membered heteroaryl) -O- (C1-C12) aliphatic-,
(5- to 10-membered heteroaryl) -N (R'')-(C1-C12) aliphatic-,
(3-10 member heterocyclyl)-(C1-C12) Aliphatic-,
(3-10 member heterocyclyl) -O- (C1-C12) aliphatic-and
(3-10 member heterocyclyl) -N (R'')-(C1-C12) Aliphatic-
Selected from
Here R ² Are independently replaced by 0-5 R';
R ³ teeth:
-(C1-C6) alkyl,-(C2-C6) alkenyl, -C≡CH, -CN, halogen, -SO ₂ ((C6 to C10) -aryl), -SO _{2 (} (C1-C6) alkyl), -C (O) N ((C1-C6) alkyl) ₂ , -C (O) NH ₂ , -C (O) O ((C1-C6) alkyl), -C (O) ((C1-C6) alkyl),-(C6-C10) aryl, 5-membered to 10-membered heteroaryl, 5-membered to Selected from 10 members of heterocyclyl, where R ³ Are independently replaced by 0-5 R';
R ⁴ And R ⁵ Are independently selected from -H, halogen and-(C1-C6) alkyl;
R ⁶ Is selected from -H and-(C1-C6) alkyl;
Each R is independent:
H-,
(C1-C12) -aliphatic-,
(C3 to C10) -Cycloalkyl-,
(C3 to C10) -Cycloalkenyl-,
[(C3 to C10) -cycloalkyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkyl] -O- (C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl] -O- (C1 to C12) -aliphatic-,
(C6 to C10) -aryl-,
(C6 to C10) -aryl- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-O- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-N (R'')-(C1 to C12) aliphatic-,
Heterocyclyl of 3 to 10 members-,
(3-10 member heterocyclyl)-(C1-C12) Aliphatic-,
(3-10 member heterocyclyl) -O- (C1-C12) aliphatic-,
(3-10 member heterocyclyl) -N (R'')-(C1-C12) aliphatic-,
5-10 member heteroaryl-,
(5- to 10-membered heteroaryl)-(C1-C12) -aliphatic-,
(5- to 10-membered heteroaryl) -O- (C1-C12) -aliphatic-; and
(5- to 10-membered heteroaryl) -N (R'')-(C1-C12) -aliphatic-
Selected from;
Here, the heterocyclyl is N, NH, O, S, SO, and SO. ₂ Has 1 to 4 heteroatoms independently selected from, and the heteroaryl has 1 to 4 heteroatoms independently selected from N, NH, O, and S. death;
Where each existence of R is independently replaced by 0-5 R';
Alternatively, if two R groups are attached to the same atom, the two R groups together with the atom to which they are attached are N, NH, O, S, SO, and SO. ₂ Can form a 3- to 10-membered aromatic or non-aromatic ring with 0-4 heteroatoms independently selected from, where the ring is 0-5 R'. The ring is optionally substituted with, and the ring is required for (C6-C10) aryl, 5-membered to 10-membered heteroaryl, (C3-C10) cycloalkyl, or 3-membered to 10-membered heterocyclyl. Condensed accordingly;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, and -CH. ₂ OR'', -CH ₂ NR'''' ₂ , -C (O) N (R'') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ And -N (R'') ₂ Selected from;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-. , (C6 to C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1-C6) -alkyl-, (5-membered) Selected from 10-membered heteroaryl) -O- (C1-C6) -alkyl- and (C6-C10) -aryl-O- (C1-C6) -alkyl-.
A compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.
(Item 3)
Equation IV:

Compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, in formula IV:
m is 0 to 3;
Each R ¹ Halogen, -H,-(C1-C6) alkyl, -C≡CH, -OH, -O ((C1-C6) alkyl), -NO independently ₂ , -CN, -CF ₃ , -OCF ₃ Selected from, here R ¹ Are independently replaced by 0-5 R';
R ² Is -OR ⁸ , -SR ⁸ ,-(CH ₂ ) _n OR ⁸ ,-(CH ₂ ) _n O (CH ₂ ) _n R ⁸ ,-(CH ₂ ) _p R ⁸ And-(CH ₂ ) _n N (R'') R ¹⁰ Selected from, where n is an integer selected from 0 to 4; p is an integer selected from 2 to 4; each R ⁸ Are independently -(C1-C6) alkyl,-(C3-C10) -cycloalkyl, (C6-C10) -aryl, or 5- to 10-membered heteroaryl, where R ⁸ Each existence of is independently replaced by 0-5 R'; each R ¹⁰ Are independently-(C3-C10) -cycloalkyl, 3-member to 10-membered heterocyclyl-, (C6-C10) -aryl, or 5- to 10-membered heteroaryl, where R ¹⁰ Each existence of is independently replaced by 0-5 R'; where R ² Are independently replaced by 0-5 R';
R ³ teeth:
-H, -CN, halogen (eg Br),-(C1-C6) alkyl, -C≡CH, -SO _{2 (} (C1-C6) alkyl), -C (O) N ((C1-C6) alkyl) ₂ ,), -C (O) NH ((C1-C6) aliphatic) ₂ , (C6 to C10) -aryl- (C1-C12) aliphatic-, -C (O) ((C1-C6) alkyl), -C (O) O ((C1-C6) alkyl), 5 members or Selected from 6-membered heterocyclyls and 5- or 6-membered heteroaryls; where R ³ Are independently replaced by 0-5 R';
R ⁴ And R ⁵ Are independently selected from -H, halogen and-(C1-C6) alkyl;
R ⁶ Is selected from -H and-(C1-C6) alkyl;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, and -CH. ₂ OR'', -CH ₂ NR'''' ₂ , -C (O) N (R'') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ And -N (R'') ₂ Selected from;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-. , (C6 to C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1-C6) -alkyl-, (5-membered) Selected from 10-membered heteroaryl) -O- (C1-C6) -alkyl- and (C6-C10) -aryl-O- (C1-C6) -alkyl-.
A compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.
(Item 4)

A compound selected from, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.
(Item 5)

A compound selected from, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.
(Item 6)
The compound according to any one of items 1 to 5 of the therapeutically effective amount or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof; and an acceptable carrier, adjuvant. Or a pharmaceutical composition comprising a vehicle.
(Item 7)
6. The pharmaceutical composition according to item 6, wherein the composition further comprises a second therapeutic agent.
(Item 8)
7. The pharmaceutical composition of item 7, wherein the second therapeutic agent is selected from antipsychotics, memantine and acetylcholinesterase inhibitors (AChE-I).
(Item 9)
7. The pharmacy according to item 7, wherein the second therapeutic agent is an antipsychotic agent selected from aripiprazole, olanzapine and ziprasidone and pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof. Composition.
(Item 10)
7. The pharmaceutical composition according to item 7, wherein the second therapeutic agent is memantine, a pharmaceutically acceptable salt thereof, a hydrate, a solvate or a polymorph.
(Item 11)
7. The pharmacy according to item 7, wherein the second therapeutic agent is AChE-I selected from donepezil, galantamine and rivastigmine and pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof. Composition.
(Item 12)
A method for treating cognitive deficits associated with CNS disorders in a subject in need of treatment for cognitive deficits associated with central nervous system (CNS) disorders, wherein the compound according to any one of items 1 to 5. A method comprising the step of administering the pharmaceutical composition according to any one of items 6 to 11.
(Item 13)
The method according to item 12, wherein the CNS disorder is an age-related cognitive disorder.
(Item 14)
13. The method of item 13, wherein the age-related cognitive impairment is mild cognitive impairment (MCI).
(Item 15)
The method according to item 14, wherein the mild cognitive impairment is amnestic mild cognitive impairment (AMCI).
(Item 16)
The method according to item 12, wherein the CNS disorder is dementia.
(Item 17)
The method according to item 16, wherein the dementia is Alzheimer's disease.
(Item 18)
12. The method of item 12, wherein the CNS disorder is schizophrenia or bipolar disorder.
(Item 19)
The method of item 12, wherein the CNS disorder is amyotrophic lateral sclerosis (ALS).
(Item 20)
The method of item 12, wherein the CNS disorder is post-traumatic stress disorder (PTSD).
(Item 21)
12. The method of item 12, wherein the CNS disorder is associated with cancer treatment.
(Item 22)
12. The method of item 12, wherein the CNS disorder is mental retardation.
(Item 23)
12. The method of item 12, wherein the CNS disorder is Parkinson's disease (PD).
(Item 24)
12. The method of item 12, wherein the CNS disorder is autism.
(Item 25)
12. The method of item 12, wherein the CNS disorder is obsessive-compulsive behavior.
(Item 26)
The method according to item 12, wherein the CNS disorder is a substance addiction.
(Item 27)
The compound according to any one of items 1 to 5 for use as a pharmaceutical.
(Item 28)
Item 6. Compound.
(Item 29)
28. The compound for use, wherein the CNS disorder is an age-related cognitive disorder.
(Item 30)
29. The compound for use, wherein the age-related cognitive impairment is mild cognitive impairment (MCI).
(Item 31)
The compound for use according to item 30, wherein the mild cognitive impairment is amnestic mild cognitive impairment (AMCI).
(Item 32)
28. The compound for use, wherein the CNS disorder is dementia.
(Item 33)
The compound according to item 32, wherein the dementia is Alzheimer's disease.
(Item 34)
28. The compound for use, wherein the CNS disorder is schizophrenia or bipolar disorder.
(Item 35)
28. The compound for use, wherein the CNS disorder is amyotrophic lateral sclerosis (ALS).
(Item 36)
28. The compound for use, wherein the CNS disorder is post-traumatic stress disorder (PTSD).
(Item 37)
28. The compound for use, wherein the CNS disorder is associated with cancer treatment.
(Item 38)
28. The compound for use, wherein the CNS disorder is mental retardation.
(Item 39)
28. The compound for use, wherein the CNS disorder is Parkinson's disease (PD).
(Item 40)
28. The compound for use, wherein the CNS disorder is autism.
(Item 41)
28. The compound for use, wherein the CNS disorder is obsessive-compulsive behavior.
(Item 42)
28. The compound for use, wherein the CNS disorder is a substance addiction.
(Item 43)
Item 6. Use of a compound or the pharmaceutical composition according to any one of items 6-11.
(Item 44)
43. The use according to item 43, wherein the CNS disorder is an age-related cognitive disorder.
(Item 45)
44. The use according to item 44, wherein the age-related cognitive impairment is mild cognitive impairment (MCI).
(Item 46)
The use according to item 45, wherein the mild cognitive impairment is amnestic mild cognitive impairment (AMCI).
(Item 47)
The use according to item 43, wherein the CNS disorder is dementia.
(Item 48)
47. The use according to item 47, wherein the dementia is Alzheimer's disease.
(Item 49)
43. The use according to item 43, wherein the CNS disorder is schizophrenia or bipolar disorder.
(Item 50)
43. The use according to item 43, wherein the CNS disorder is amyotrophic lateral sclerosis (ALS).
(Item 51)
43. The use according to item 43, wherein the CNS disorder is post-traumatic stress disorder (PTSD).
(Item 52)
The use according to item 43, wherein the CNS disorder is associated with cancer treatment.
(Item 53)
The use according to item 43, wherein the CNS disorder is mental retardation.
(Item 54)
43. The use according to item 43, wherein the CNS disorder is Parkinson's disease (PD).
(Item 55)
The use according to item 43, wherein the CNS disorder is autism.
(Item 56)
The use according to item 43, wherein the CNS disorder is obsessive-compulsive behavior.
(Item 57)
The use according to item 43, wherein the CNS disorder is a substance addiction.
Abstract of the invention
The present invention describes the formula I:

The above need is addressed by providing the compounds of, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof. In Equation I:
U and the two carbon atoms represented by α and β together form a 5- or 6-membered aromatic ring with 0 to 2 nitrogen atoms;
A is C, CR⁶, Or N;
B and F are independent of C and CR, respectively.⁶, And N, where both B and F cannot be N;
D is N, NR⁷, O, CR⁶Or C (R⁶)₂And;
E is N, NR⁷, CR⁶Or C (R⁶)₂And;
W is N, NR⁷, CR⁶Or C (R⁶)₂And;
X is N, NR⁷, O, CR⁶Or C (R⁶)₂And;
Y and Z are independent of C and CR, respectively.⁶, And N, where both Y and Z cannot be N;
V is C or CR⁶Is it?
Or Z is C or CR⁶If, V is C, CR⁶, Or N;
Here the ring formed by X, Y, Z, V and W

If, then R²Is -OR⁸, -SR⁸,-(CH₂)_nOR⁸,-(CH₂)_nO (CH₂)_nR⁸,-(CH₂)_pR⁸And-(CH₂)_nN (R ″) R¹⁰And here R²Are independently replaced by 0-5 R';
m and n are integers independently selected from 0 to 4;
p is an integer selected from 2-4;
Join

Each presence of is either a single bond or a double bond;
R¹, R², R⁴, And R⁵Each being is independent of:
Halogen, -R, -OR, -NO₂, -NCS, -CN, -CF₃, -OCF₃, -SiR₃, -N (R)₂, -SR, -SOR, -SO₂R, -SO₂N (R)₂, -SO₃R,-(CR₂)_1-3R,-(CR₂)_1-3-OR,-(CR₂)_0-3-C (O) NR (CR)₂)_0-3R,-(CR₂)_0-3-C (O) NR (CR)₂)_0-3OR, -C (O) R, -C (O) C (O) R, -C (O) CH₂C (O) R, -C (S) R, -C (S) OR, -C (O) OR, -C (O) C (O) OR, -C (O) C (O) N (R) )₂, -OC (O) R, -C (O) N (R)₂, -OC (O) N (R)₂, -C (S) N (R)₂,-(CR₂)_0-3NHC (O) R, -N (R) N (R) COR, -N (R) N (R) C (O) OR, -N (R) N (R) CON (R)₂, -N (R) SO₂R, -N (R) SO₂N (R)₂, -N (R) C (O) OR, -N (R) C (O) R, -N (R) C (S) R, -N (R) C (O) N (R)₂, -N (R) C (S) N (R)₂, -N (COR) COR, -N (OR) R, -C (= NH) N (R)₂, -C (O) N (OR) R, -C (= NOR) R, -OP (O) (OR)₂, -P (O) (R)₂, -P (O) (OR)₂, And -P (O) (H) (OR)
Selected from;
R³Does not exist or:
Halogen, -R, -OR, -NO₂, -NCS, -CN, -CF₃, -OCF₃, -SiR₃, -N (R)₂, -SR, -SOR, -SO₂R, -SO₂N (R)₂, -SO₃R,-(CR₂)_1-3R,-(CR₂)_1-3-OR,-(CR₂)_0-3-C (O) NR (CR)₂)_0-3R,-(CR₂)_0-3-C (O) NR (CR)₂)_0-3OR, -C (O) R, -C (O) C (O) R, -C (O) CH₂C (O) R, -C (S) R, -C (S) OR, -C (O) OR, -C (O) C (O) OR, -C (O) C (O) N (R) )₂, -OC (O) R, -C (O) N (R)₂, -OC (O) N (R)₂, -C (S) N (R)₂,-(CR₂)_0-3NHC (O) R, -N (R) N (R) COR, -N (R) N (R) C (O) OR, -N (R) N (R) CON (R)₂, -N (R) SO₂R, -N (R) SO₂N (R)₂, -N (R) C (O) OR, -N (R) C (O) R, -N (R) C (S) R, -N (R) C (O) N (R)₂, -N (R) C (S) N (R)₂, -N (COR) COR, -N (OR) R, -C (= NH) N (R)₂, -C (O) N (OR) R, -C (= NOR) R, -OP (O) (OR)₂, -P (O) (R)₂, -P (O) (OR)₂, And -P (O) (H) (OR)
Selected from;
Each R⁶Are independently -H or-(C1-C6) alkyl;
Each R⁷Are independently -H or-(C1-C6) alkyl;
Each R⁸Are independently -(C1-C6) alkyl,-(C3-C10) -cycloalkyl, (C6-C10) -aryl, or 5- to 10-membered heteroaryl, where R⁸Each existence of is independently replaced by 0-5 R';
Each R¹⁰Are independently-(C3-C10) -cycloalkyl, 3-member to 10-membered heterocyclyl-, (C6-C10) -aryl, or 5- to 10-membered heteroaryl, where R¹⁰Each existence of is independently replaced by 0-5 R';
Each R is independent:
H-,
(C1-C12) -aliphatic-,
(C3 to C10) -Cycloalkyl-,
(C3 to C10) -Cycloalkenyl-,
[(C3 to C10) -cycloalkyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkyl] -O- (C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl] -O- (C1 to C12) -aliphatic-,
(C6 to C10) -aryl-,
(C6 to C10) -aryl- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-O- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-N (R ″)-(C1 to C12) aliphatic-,
Heterocyclyl of 3 to 10 members-,
(3-10 member heterocyclyl)-(C1-C12) Aliphatic-,
(3-10 member heterocyclyl) -O- (C1-C12) aliphatic-,
(3-10 member heterocyclyl) -N (R ")-(C1-C12) aliphatic-,
5-10 member heteroaryl-,
(5- to 10-membered heteroaryl)-(C1-C12) -aliphatic-,
(5- to 10-membered heteroaryl) -O- (C1-C12) -aliphatic-; and
(5- to 10-membered heteroaryl) -N (R ")-(C1-C12) -aliphatic-
Selected from;
Here, this heterocyclyl is N, NH, O, S, SO, and SO.₂Has 1 to 4 heteroatoms independently selected from, and this heteroaryl has 1 to 4 heteroatoms independently selected from N, NH, O, and S. death;
Where each existence of R is independently replaced by 0-5 R';
Alternatively, if two R groups are attached to the same atom, these two R groups, together with the atom to which they are attached, are N, NH, O, S, SO, and SO.₂Can form a 3- to 10-membered aromatic or non-aromatic ring with 0-4 heteroatoms independently selected from, where the ring is 0-5 R'. The ring is optionally substituted with, and this ring is required for (C6-C10) aryl, 5-membered to 10-membered heteroaryl, (C3-C10) cycloalkyl, or 3-membered to 10-membered heterocyclyl. Condensed accordingly;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, and -CH.₂OR ″, -CH₂NR ″₂, -C (O) N (R ″)₂, -C (O) OR ", -NO₂, -NCS, -CN, -CF₃, -OCF₃And -N (R ″)₂Selected from;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl,-(C1-C6) -aliphatic, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl. 5, 10-membered heteroaryl-, (C6-C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1) ~ C6) -alkyl-, (5- to 10-membered heteroaryl) -O- (C1-C6) -alkyl-, and (C6-C10) -aryl-O- (C1-C6) -alkyl- And here each presence of R'' is halogen, -R^o, -OR^o, Oxo, -CH₂OR^o, -CH₂NR^o ₂, -C (O) N (R)^o)₂, -C (O) OR^o, -NO₂, -NCS, -CN, -CF₃, -OCF₃And -N (R^o)₂It is independently substituted with 0 to 3 substituents selected from, where R^oIndependently, each presence of-(C1-C6) -aliphatic, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-, and (C6-C10). ) -Aryl-is selected.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式Ｉにおいて：
Ｕと、αおよびβによって表される２個の炭素原子とが一緒になって、０個〜２個の窒素原子を有する５員または６員の芳香環を形成し；
Ａは、Ｃ、ＣＲ^６、またはＮであり；
ＢおよびＦは各々独立して、Ｃ、ＣＲ^６、およびＮから選択され、ここでＢとＦとの両方がＮであることはできず；
Ｄは、Ｎ、ＮＲ^７、Ｏ、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｅは、Ｎ、ＮＲ^７、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｗは、Ｎ、ＮＲ^７、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｘは、Ｎ、ＮＲ^７、Ｏ、ＣＲ^６またはＣ（Ｒ^６）_２であり；
ＹおよびＺは各々独立して、Ｃ、ＣＲ^６、およびＮから選択され、ここでＹとＺとの両方がＮであることはできず；
Ｖは、ＣまたはＣＲ^６であるか、
あるいはＺがＣまたはＣＲ^６である場合、Ｖは、Ｃ、ＣＲ^６、またはＮであり；
ここでＸ、Ｙ、Ｚ、ＶおよびＷによって形成される環が

である場合、Ｒ^２は、−ＯＲ^８、−ＳＲ^８、−（ＣＨ_２）_ｎＯＲ^８、−（ＣＨ_２）_ｎＯ（ＣＨ_２）_ｎＲ^８、−（ＣＨ_２）_ｐＲ^８および−（ＣＨ_２）_ｎＮ（Ｒ’’）Ｒ^１０であり；ここでＲ^２は独立して、０個〜５個のＲ’で置換されており；
ｍおよびｎは独立して、０〜４から選択される整数であり；
ｐは、２〜４から選択される整数であり；
結合

の各存在は、単結合または二重結合のいずれかであり；
Ｒ^１、Ｒ^２、Ｒ^４、およびＲ^５の各存在は、各々独立して：
ハロゲン、−Ｒ、−ＯＲ、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３、−ＳｉＲ_３、−Ｎ（Ｒ）_２、−ＳＲ、−ＳＯＲ、−ＳＯ_２Ｒ、−ＳＯ_２Ｎ（Ｒ）_２、−ＳＯ_３Ｒ、−（ＣＲ_２）_１〜３Ｒ、−（ＣＲ_２）_１〜３−ＯＲ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３Ｒ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３ＯＲ、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＣＨ_２Ｃ（Ｏ）Ｒ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｎ（Ｒ）_２、−Ｃ（Ｓ）Ｎ（Ｒ）_２、−（ＣＲ_２）_０〜３ＮＨＣ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＮ（Ｒ）_２、−Ｎ（Ｒ）ＳＯ_２Ｒ、−Ｎ（Ｒ）ＳＯ_２Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｓ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｓ）Ｎ（Ｒ）_２、−Ｎ（ＣＯＲ）ＣＯＲ、−Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＨ）Ｎ（Ｒ）_２、−Ｃ（Ｏ）Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＯＲ）Ｒ、−ＯＰ（Ｏ）（ＯＲ）_２、−Ｐ（Ｏ）（Ｒ）_２、−Ｐ（Ｏ）（ＯＲ）_２、および−Ｐ（Ｏ）（Ｈ）（ＯＲ）
から選択され；
Ｒ^３は、存在しないか、または：
ハロゲン、−Ｒ、−ＯＲ、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３、−ＳｉＲ_３、−Ｎ（Ｒ）_２、−ＳＲ、−ＳＯＲ、−ＳＯ_２Ｒ、−ＳＯ_２Ｎ（Ｒ）_２、−ＳＯ_３Ｒ、−（ＣＲ_２）_１〜３Ｒ、−（ＣＲ_２）_１〜３−ＯＲ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３Ｒ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３ＯＲ、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＣＨ_２Ｃ（Ｏ）Ｒ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｎ（Ｒ）_２、−Ｃ（Ｓ）Ｎ（Ｒ）_２、−（ＣＲ_２）_０〜３ＮＨＣ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＮ（Ｒ）_２、−Ｎ（Ｒ）ＳＯ_２Ｒ、−Ｎ（Ｒ）ＳＯ_２Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｓ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｓ）Ｎ（Ｒ）_２、−Ｎ（ＣＯＲ）ＣＯＲ、−Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＨ）Ｎ（Ｒ）_２、−Ｃ（Ｏ）Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＯＲ）Ｒ、−ＯＰ（Ｏ）（ＯＲ）_２、−Ｐ（Ｏ）（Ｒ）_２、−Ｐ（Ｏ）（ＯＲ）_２、および−Ｐ（Ｏ）（Ｈ）（ＯＲ）
から選択され；
各Ｒ^６は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
各Ｒ^７は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
各Ｒ^８は独立して、−（Ｃ１〜Ｃ６）アルキル、−（Ｃ３〜Ｃ１０）−シクロアルキル、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ^８の各存在は独立して、０個〜５個のＲ’で置換されており；
各Ｒ^１０は独立して、−（Ｃ３〜Ｃ１０）−シクロアルキル、３員〜１０員のヘテロシクリル−、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ^１０の各存在は独立して、０個〜５個のＲ’で置換されており；
各Ｒは独立して：
Ｈ−、
（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ３〜Ｃ１０）−シクロアルキル−、
（Ｃ３〜Ｃ１０）−シクロアルケニル−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−、
（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
３員〜１０員のヘテロシクリル−、
（３員〜１０員のヘテロシクリル）−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
５員〜１０員のヘテロアリール−、
（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ１２）−脂肪族−、
（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−；および
（５員〜１０員のヘテロアリール）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）−脂肪族−
から選択され；
ここでこのヘテロシクリルは、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される１個〜４個のヘテロ原子を有し、そしてこのヘテロアリールは、Ｎ、ＮＨ、Ｏ、およびＳから独立して選択される１個〜４個のヘテロ原子を有し；
ここでＲの各存在は独立して、０個〜５個のＲ’で置換されているか；
あるいは２個のＲ基が同じ原子に結合している場合、これらの２個のＲ基は、これらが結合している原子と一緒になって、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される０個〜４個のヘテロ原子を有する３員〜１０員の芳香族または非芳香族の環を形成し得、ここでこの環は、０個〜５個のＲ’で必要に応じて置換されており、そしてこの環は、（Ｃ６〜Ｃ１０）アリール、５員〜１０員のヘテロアリール、（Ｃ３〜Ｃ１０）シクロアルキル、または３員〜１０員のヘテロシクリルに必要に応じて縮合しており；
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ_２ＯＲ’’、−ＣＨ_２ＮＲ’’_２、−Ｃ（Ｏ）Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ’’）_２から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択される。 Some embodiments of the present application include Formula I :.

A compound of, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, provided in Formula I:
U and the two carbon atoms represented by α and β together form a 5- or 6-membered aromatic ring with 0 to 2 nitrogen atoms;
A is C, CR ⁶ , or N;
B and F are independently ^{selected from C, CR 6} , and N, where both B and F cannot be N;
D is N, NR ⁷ , O, CR ⁶ or C (R ⁶ ) ₂ ;
E is N, NR ⁷ , CR ⁶ or C (R ⁶ ) ₂ ;
W is N, NR ⁷ , CR ⁶ or C (R ⁶ ) ₂ ;
X is N, NR ⁷ , O, CR ⁶ or C (R ⁶ ) ₂ ;
Y and Z are independently ^{selected from C, CR 6} , and N, where both Y and Z cannot be N;
V is C or CR ⁶ or
Alternatively, if Z is C or CR ⁶ , then V is C, CR ⁶ , or N;
Here the ring formed by X, Y, Z, V and W

If, then R ² is −OR ⁸ , −SR ⁸ , − (CH ₂ ) _n OR ⁸ , − (CH ₂ ) _n O (CH ₂ ) _n R ⁸ , − (CH ₂ ) _p R ⁸ and − (CH ₂ ) _n N (R'') R ¹⁰ ; where R ² is independently substituted with 0-5 R';
m and n are integers independently selected from 0 to 4;
p is an integer selected from 2-4;
Join

Each presence of is either a single bond or a double bond;
The ^{existence of R 1} , R ² , R ⁴ , and R ⁵ is independent of each other:
Halogen, -R, -OR, -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ , -SiR ₃ , -N (R) ₂ , -SR, -SOR, -SO ₂ R, -SO ₂ N (R) ₂ , -SO ₃ R,-(CR ₂ ) _1-3 R,-(CR ₂ ) _1-3- OR,-(CR ₂ ) _0-3 -C (O) NR (CR ₂₎ ) _0-3 R,-(CR ₂ ) _0-3 -C (O) NR (CR ₂ ) _0-3 OR, -C (O) R, -C (O) C (O) R, -C ( O) CH ₂ C (O) R, -C (S) R, -C (S) OR, -C (O) OR, -C (O) C (O) OR, -C (O) C (O) ) N (R) ₂ , -OC (O) R, -C (O) N (R) ₂ , -OC (O) N (R) ₂ , -C (S) N (R) ₂ ,-(CR) ₂ ) _{0 to 3} NHC (O) R, -N (R) N (R) COR, -N (R) N (R) C (O) OR, -N (R) N (R) CON (R) ₂ , -N (R) SO ₂ R, -N (R) SO ₂ N (R) ₂ , -N (R) C (O) OR, -N (R) C (O) R, -N (R) ) C (S) R, -N (R) C (O) N (R) ₂ , -N (R) C (S) N (R) ₂ , -N (COR) COR, -N (OR) R , -C (= NH) N (R) ₂ , -C (O) N (OR) R, -C (= NOR) R, -OP (O) (OR) ₂ , -P (O) (R) ₂ , -P (O) (OR) ₂ , and -P (O) (H) (OR)
Selected from;
R ³ does not exist or:
Halogen, -R, -OR, -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ , -SiR ₃ , -N (R) ₂ , -SR, -SOR, -SO ₂ R, -SO ₂ N (R) ₂ , -SO ₃ R,-(CR ₂ ) _1-3 R,-(CR ₂ ) _1-3- OR,-(CR ₂ ) _0-3 -C (O) NR (CR ₂₎ ) _0-3 R,-(CR ₂ ) _0-3 -C (O) NR (CR ₂ ) _0-3 OR, -C (O) R, -C (O) C (O) R, -C ( O) CH ₂ C (O) R, -C (S) R, -C (S) OR, -C (O) OR, -C (O) C (O) OR, -C (O) C (O) ) N (R) ₂ , -OC (O) R, -C (O) N (R) ₂ , -OC (O) N (R) ₂ , -C (S) N (R) ₂ ,-(CR) ₂ ) _{0 to 3} NHC (O) R, -N (R) N (R) COR, -N (R) N (R) C (O) OR, -N (R) N (R) CON (R) ₂ , -N (R) SO ₂ R, -N (R) SO ₂ N (R) ₂ , -N (R) C (O) OR, -N (R) C (O) R, -N (R) ) C (S) R, -N (R) C (O) N (R) ₂ , -N (R) C (S) N (R) ₂ , -N (COR) COR, -N (OR) R , -C (= NH) N (R) ₂ , -C (O) N (OR) R, -C (= NOR) R, -OP (O) (OR) ₂ , -P (O) (R) ₂ , -P (O) (OR) ₂ , and -P (O) (H) (OR)
Selected from;
Each ^{R 6} is independently, -H or - be (C1 -C6) alkyl;
Each R ⁷ is independently -H or- (C1-C6) alkyl;
Each R ⁸ is independently a-(C1-C6) alkyl,-(C3-C10) -cycloalkyl, (C6-C10) -aryl, or 5- to 10-membered heteroaryl, where R ^{8 is.} Each existence of is independently replaced by 0-5 R';
Each R ¹⁰ is independently a-(C3-C10) -cycloalkyl, 3-member to 10-membered heterocyclyl-, (C6-C10) -aryl, or 5- to 10-membered heteroaryl, where R ^{Each of the 10} beings is independently replaced by 0-5 R';
Each R is independent:
H-,
(C1-C12) -aliphatic-,
(C3 to C10) -Cycloalkyl-,
(C3 to C10) -Cycloalkenyl-,
[(C3 to C10) -cycloalkyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkyl] -O- (C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl] -O- (C1 to C12) -aliphatic-,
(C6 to C10) -aryl-,
(C6 to C10) -aryl- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-O- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-N (R'')-(C1 to C12) aliphatic-,
Heterocyclyl of 3 to 10 members-,
(3-10 member heterocyclyl)-(C1-C12) Aliphatic-,
(3-10 member heterocyclyl) -O- (C1-C12) aliphatic-,
(3-10 member heterocyclyl) -N (R'')-(C1-C12) aliphatic-,
5-10 member heteroaryl-,
(5- to 10-membered heteroaryl)-(C1-C12) -aliphatic-,
(5-membered to 10-membered heteroaryl) -O- (C1-C12) -aliphatic-; and (5-membered to 10-membered heteroaryl) -N (R'')-(C1-C12) -aliphatic −
Selected from;
Here the heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO ₂ , and the heteroaryl is N, NH, O, And has 1 to 4 heteroatoms selected independently of S;
Where each existence of R is independently replaced by 0-5 R';
Alternatively, if two R groups are attached to the same atom, these two R groups, together with the atom to which they are attached, are N, NH, O, S, SO, and SO. It is possible to form a 3- to 10-membered aromatic or non-aromatic ring with 0 to 4 heteroatoms independently selected from _{2, where the ring is 0 to 5 Rs.} 'Is substituted as needed, and this ring is required for (C6-C10) aryl, 5-membered to 10-membered heteroaryl, (C3-C10) cycloalkyl, or 3-membered to 10-membered heterocyclyl. Condensed according to;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, -CH ₂ OR " _{, -CH 2} NR" ₂ , and -C (O) N (R'. ') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R') ₂ ;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-. , (C6 to C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1-C6) -alkyl-, (5-membered) It is selected from 10-membered heteroaryl) -O- (C1-C6) -alkyl- and (C6-C10) -aryl-O- (C1-C6) -alkyl-.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式Ｉにおいて：
Ｕと、αおよびβによって表される２個の炭素原子とが一緒になって、０個〜２個の窒素原子を有する５員または６員の芳香環を形成し；
Ａは、Ｃ、ＣＲ^６、またはＮであり；
ＢおよびＦは各々独立して、Ｃ、ＣＲ^６、およびＮから選択され、ここでＢとＦとの両方がＮであることはできず；
Ｄは、Ｎ、ＮＲ^７、Ｏ、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｅは、Ｎ、ＮＲ^７、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｗは、Ｎ、ＮＲ^７、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｘは、Ｎ、ＮＲ^７、Ｏ、ＣＲ^６またはＣ（Ｒ^６）_２であり；
ＹおよびＺは各々独立して、Ｃ、ＣＲ^６、およびＮから選択され、ここでＹとＺとの両方がＮであることはできず；
Ｖは、ＣまたはＣＲ^６であるか、
あるいはＺがＣまたはＣＲ^６である場合、Ｖは、Ｃ、ＣＲ^６、またはＮであり；
ここでＸ、Ｙ、Ｚ、ＶおよびＷによって形成される環が

である場合、Ｒ^２は、−ＯＲ^８、−ＳＲ^８、または−（ＣＨ_２）_ｎＯＲ^８であり；
ｍおよびｎは独立して、０〜４から選択される整数であり；
結合

の各存在は、単結合または二重結合のいずれかであり；
Ｒ^１、Ｒ^２、Ｒ^４、およびＲ^５の各存在は、各々独立して：
ハロゲン、−Ｒ、−ＯＲ、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３、−ＳｉＲ_３、−Ｎ（Ｒ）_２、−ＳＲ、−ＳＯＲ、−ＳＯ_２Ｒ、−ＳＯ_２Ｎ（Ｒ）_２、−ＳＯ_３Ｒ、−（ＣＲ_２）_１〜３Ｒ、−（ＣＲ_２）_１〜３−ＯＲ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３Ｒ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３ＯＲ、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＣＨ_２Ｃ（Ｏ）Ｒ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｎ（Ｒ）_２、−Ｃ（Ｓ）Ｎ（Ｒ）_２、−（ＣＲ_２）_０〜３ＮＨＣ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＮ（Ｒ）_２、−Ｎ（Ｒ）ＳＯ_２Ｒ、−Ｎ（Ｒ）ＳＯ_２Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｓ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｓ）Ｎ（Ｒ）_２、−Ｎ（ＣＯＲ）ＣＯＲ、−Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＨ）Ｎ（Ｒ）_２、−Ｃ（Ｏ）Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＯＲ）Ｒ、−ＯＰ（Ｏ）（ＯＲ）_２、−Ｐ（Ｏ）（Ｒ）_２、−Ｐ（Ｏ）（ＯＲ）_２、および−Ｐ（Ｏ）（Ｈ）（ＯＲ）
から選択され；
Ｒ^３は、存在しないか、または：
ハロゲン、−Ｒ、−ＯＲ、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３、−ＳｉＲ_３、−Ｎ（Ｒ）_２、−ＳＲ、−ＳＯＲ、−ＳＯ_２Ｒ、−ＳＯ_２Ｎ（Ｒ）_２、−ＳＯ_３Ｒ、−（ＣＲ_２）_１〜３Ｒ、−（ＣＲ_２）_１〜３−ＯＲ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３Ｒ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３ＯＲ、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＣＨ_２Ｃ（Ｏ）Ｒ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｎ（Ｒ）_２、−Ｃ（Ｓ）Ｎ（Ｒ）_２、−（ＣＲ_２）_０〜３ＮＨＣ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＮ（Ｒ）_２、−Ｎ（Ｒ）ＳＯ_２Ｒ、−Ｎ（Ｒ）ＳＯ_２Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｓ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｓ）Ｎ（Ｒ）_２、−Ｎ（ＣＯＲ）ＣＯＲ、−Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＨ）Ｎ（Ｒ）_２、−Ｃ（Ｏ）Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＯＲ）Ｒ、−ＯＰ（Ｏ）（ＯＲ）_２、−Ｐ（Ｏ）（Ｒ）_２、−Ｐ（Ｏ）（ＯＲ）_２、および−Ｐ（Ｏ）（Ｈ）（ＯＲ）
から選択され；
各Ｒ^６は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
各Ｒ^７は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
各Ｒ^８は独立して、−（Ｃ１〜Ｃ６）アルキル、−（Ｃ３〜Ｃ１０）−シクロアルキル、−（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ^８の各存在は独立して、０個〜５個のＲ’で置換されており；
各Ｒは独立して：
Ｈ−、
（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ３〜Ｃ１０）−シクロアルキル−、
（Ｃ３〜Ｃ１０）−シクロアルケニル−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−、
（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
３員〜１０員のヘテロシクリル−、
（３員〜１０員のヘテロシクリル）−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
５員〜１０員のヘテロアリール−、
（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ１２）−脂肪族−、および
（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−
から選択され；
ここでこのヘテロシクリルは、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される１個〜４個のヘテロ原子を有し、そしてこのヘテロアリールは、Ｎ、ＮＨ、Ｏ、およびＳから独立して選択される１個〜４個のヘテロ原子を有し；
ここでＲの各存在は独立して、０個〜５個のＲ’で置換されているか；
あるいは２個のＲ基が同じ原子に結合している場合、これらの２個のＲ基は、これらが結合している原子と一緒になって、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される０個〜４個のヘテロ原子を有する３員〜１０員の芳香族または非芳香族の環を形成し得、ここでこの環は、０個〜５個のＲ’で必要に応じて置換されており、そしてこの環は、（Ｃ６〜Ｃ１０）アリール、５員〜１０員のヘテロアリール、（Ｃ３〜Ｃ１０）シクロアルキル、または３員〜１０員のヘテロシクリルに必要に応じて縮合しており；
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ_２ＯＲ’’、−ＣＨ_２ＮＲ’’_２、−Ｃ（Ｏ）Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ’’）_２から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択される。 Some embodiments of the present application include Formula I :.

A compound of, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, provided in Formula I:
U and the two carbon atoms represented by α and β together form a 5- or 6-membered aromatic ring with 0 to 2 nitrogen atoms;
A is C, CR ⁶ , or N;
B and F are independently ^{selected from C, CR 6} , and N, where both B and F cannot be N;
D is N, NR ⁷ , O, CR ⁶ or C (R ⁶ ) ₂ ;
E is N, NR ⁷ , CR ⁶ or C (R ⁶ ) ₂ ;
W is N, NR ⁷ , CR ⁶ or C (R ⁶ ) ₂ ;
X is N, NR ⁷ , O, CR ⁶ or C (R ⁶ ) ₂ ;
Y and Z are independently ^{selected from C, CR 6} , and N, where both Y and Z cannot be N;
V is C or CR ⁶ or
Alternatively, if Z is C or CR ⁶ , then V is C, CR ⁶ , or N;
Here the ring formed by X, Y, Z, V and W

If, then R ² is −OR ⁸ , −SR ⁸ , or − (CH ₂ ) _n OR ⁸ ;
m and n are integers independently selected from 0 to 4;
Join

Each presence of is either a single bond or a double bond;
The ^{existence of R 1} , R ² , R ⁴ , and R ⁵ is independent of each other:
Halogen, -R, -OR, -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ , -SiR ₃ , -N (R) ₂ , -SR, -SOR, -SO ₂ R, -SO ₂ N (R) ₂ , -SO ₃ R,-(CR ₂ ) _1-3 R,-(CR ₂ ) _1-3- OR,-(CR ₂ ) _0-3 -C (O) NR (CR ₂₎ ) _0-3 R,-(CR ₂ ) _0-3 -C (O) NR (CR ₂ ) _0-3 OR, -C (O) R, -C (O) C (O) R, -C ( O) CH ₂ C (O) R, -C (S) R, -C (S) OR, -C (O) OR, -C (O) C (O) OR, -C (O) C (O) ) N (R) ₂ , -OC (O) R, -C (O) N (R) ₂ , -OC (O) N (R) ₂ , -C (S) N (R) ₂ ,-(CR) ₂ ) _{0 to 3} NHC (O) R, -N (R) N (R) COR, -N (R) N (R) C (O) OR, -N (R) N (R) CON (R) ₂ , -N (R) SO ₂ R, -N (R) SO ₂ N (R) ₂ , -N (R) C (O) OR, -N (R) C (O) R, -N (R) ) C (S) R, -N (R) C (O) N (R) ₂ , -N (R) C (S) N (R) ₂ , -N (COR) COR, -N (OR) R , -C (= NH) N (R) ₂ , -C (O) N (OR) R, -C (= NOR) R, -OP (O) (OR) ₂ , -P (O) (R) ₂ , -P (O) (OR) ₂ , and -P (O) (H) (OR)
Selected from;
R ³ does not exist or:
Halogen, -R, -OR, -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ , -SiR ₃ , -N (R) ₂ , -SR, -SOR, -SO ₂ R, -SO ₂ N (R) ₂ , -SO ₃ R,-(CR ₂ ) _1-3 R,-(CR ₂ ) _1-3- OR,-(CR ₂ ) _0-3 -C (O) NR (CR ₂₎ ) _0-3 R,-(CR ₂ ) _0-3 -C (O) NR (CR ₂ ) _0-3 OR, -C (O) R, -C (O) C (O) R, -C ( O) CH ₂ C (O) R, -C (S) R, -C (S) OR, -C (O) OR, -C (O) C (O) OR, -C (O) C (O) ) N (R) ₂ , -OC (O) R, -C (O) N (R) ₂ , -OC (O) N (R) ₂ , -C (S) N (R) ₂ ,-(CR) ₂ ) _{0 to 3} NHC (O) R, -N (R) N (R) COR, -N (R) N (R) C (O) OR, -N (R) N (R) CON (R) ₂ , -N (R) SO ₂ R, -N (R) SO ₂ N (R) ₂ , -N (R) C (O) OR, -N (R) C (O) R, -N (R) ) C (S) R, -N (R) C (O) N (R) ₂ , -N (R) C (S) N (R) ₂ , -N (COR) COR, -N (OR) R , -C (= NH) N (R) ₂ , -C (O) N (OR) R, -C (= NOR) R, -OP (O) (OR) ₂ , -P (O) (R) ₂ , -P (O) (OR) ₂ , and -P (O) (H) (OR)
Selected from;
Each ^{R 6} is independently, -H or - be (C1 -C6) alkyl;
Each R ⁷ is independently -H or- (C1-C6) alkyl;
Each R ⁸ is independently a-(C1-C6) alkyl,-(C3-C10) -cycloalkyl,-(C6-C10) -aryl, or 5- to 10-membered heteroaryl, where R ^{Each existence of 8} is independently replaced by 0-5 R';
Each R is independent:
H-,
(C1-C12) -aliphatic-,
(C3 to C10) -Cycloalkyl-,
(C3 to C10) -Cycloalkenyl-,
[(C3 to C10) -cycloalkyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkyl] -O- (C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl] -O- (C1 to C12) -aliphatic-,
(C6 to C10) -aryl-,
(C6 to C10) -aryl- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-O- (C1 to C12) aliphatic-,
Heterocyclyl of 3 to 10 members-,
(3-10 member heterocyclyl)-(C1-C12) Aliphatic-,
(3-10 member heterocyclyl) -O- (C1-C12) aliphatic-,
5-10 member heteroaryl-,
(5-member to 10-membered heteroaryl)-(C1-C12) -aliphatic-and (5-member to 10-membered heteroaryl) -O- (C1-C12) -aliphatic-
Selected from;
Here the heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO ₂ , and the heteroaryl is N, NH, O, And has 1 to 4 heteroatoms selected independently of S;
Where each existence of R is independently replaced by 0-5 R';
Alternatively, if two R groups are attached to the same atom, these two R groups, together with the atom to which they are attached, are N, NH, O, S, SO, and SO. It is possible to form a 3- to 10-membered aromatic or non-aromatic ring with 0 to 4 heteroatoms independently selected from _{2, where the ring is 0 to 5 Rs.} 'Is substituted as needed, and this ring is required for (C6-C10) aryl, 5-membered to 10-membered heteroaryl, (C3-C10) cycloalkyl, or 3-membered to 10-membered heterocyclyl. Condensed according to;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, -CH ₂ OR " _{, -CH 2} NR" ₂ , and -C (O) N (R'. ') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R') ₂ ;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-. , (C6 to C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1-C6) -alkyl-, (5-membered) It is selected from 10-membered heteroaryl) -O- (C1-C6) -alkyl- and (C6-C10) -aryl-O- (C1-C6) -alkyl-.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式ＩＩにおいて、ｍ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６は、式Ｉにおいて定義されるとおりである。 In another aspect, the invention is based on Formula II :.

Compounds, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof are provided in Formula II, wherein m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in Formula I.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式ＩＩＩにおいて、ｍ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６は、式Ｉにおいて定義されるとおりである。 In another aspect, the invention is based on Formula III :.

Compounds, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof are provided in Formula III, wherein m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in Formula I.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式ＩＶにおいて、Ｒ^２は、−ＯＲ^８、−ＳＲ^８、および−（ＣＨ_２）_ｎＯＲ^８であり、ここでＲ^２は独立して、０個〜５個のＲ’で置換されており、そしてｍ、ｎ、Ｒ^１、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、およびＲ^８は、式Ｉにおいて定義されるとおりである。 In another aspect, the invention is based on Formula IV :.

A compound of, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein in Formula IV, R ² is -OR ⁸ , -SR ⁸ , and. -(CH ₂ ) _n OR ⁸ , where R ² is independently substituted with 0-5 R'and m, n, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁸ are as defined in Formula I.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式ＩＶにおいて、Ｒ^２は、−（ＣＨ_２）_ｎＯ（ＣＨ_２）_ｎＲ^８、−（ＣＨ_２）_ｐＲ^８または−（ＣＨ_２）_ｎＮ（Ｒ’’）Ｒ^１０であり、ここでＲ^２は独立して、０個〜５個のＲ’で置換されており、そしてｍ、ｎ、ｐ、Ｒ^１、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^８、Ｒ^１０、およびＲ’’は、本明細書中で定義されるとおりである。 In another aspect, the invention is based on Formula IV :.

A compound of, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein in formula IV, R ² is-(CH _{2 ) n} O (CH). ₂ ) _n R ⁸ ,-(CH ₂ ) _p R ⁸ or-(CH ₂ ) _n N (R'') R ¹⁰ , where R ² is independently 0-5 R'. Substituted, and m, n, p, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹⁰ , and R'' are as defined herein. ..

The present invention also comprises pharmaceutical compositions comprising compounds of formulas I, II, III or IV, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or combinations thereof. offer.

In some embodiments, the compound of formula I is a GABA _A α5 receptor positive allosteric modulator. In some embodiments, the compound of formula II is a GABA _A α5 receptor positive allosteric modulator. In some embodiments, the compound of formula III is a GABA _A α5 receptor positive allosteric modulator. In some embodiments, the compound of formula IV is a GABA _A α5 receptor positive allosteric modulator. Compounds of formula I, II, III or IV can be used to treat the _{pathologies described herein, for example, through activity as a GABA A α5 receptor positive allosteric modulator.}

In another aspect of the invention, a method for treating said cognitive deficits in a subject in need or at risk of cognitive deficits associated with CNS deficits is provided, the methods of which are therapeutically effective. It comprises administering to said subject an amount of a compound of the invention or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof. In some embodiments, CNS disorders associated with cognitive impairment include age-related cognitive impairment, mild cognitive impairment (MCI), forgetfulness MCI (aMCI), age-related memory impairment (AAMI), and age-related cognitive decline. (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, muscular atrophic lateral sclerosis (ALS), cognitive associated with cancer treatment Disorders, mental retardation, Parkinson's disease (PD), autism spectrum disorders, fragile X disorders, Let's syndrome, compulsive behavior and substance habits are, but are not limited to. In another aspect of the invention, a method of preserving or ameliorating cognitive function in a subject in need of prevention or improvement of cognitive function is provided, wherein the method is a therapeutically effective amount of a compound of the invention or a pharmaceutical product thereof. Includes the step of administering to said subject a generally acceptable salt, hydrate, solvate, polymorph, isomer or combination. In certain embodiments of the invention, the compounds of the invention or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or combinations thereof are administered every 12 or 24 hours. ..

In some embodiments, the compounds and compositions of the invention are for use as pharmaceuticals. In some embodiments, the compounds and compositions of the invention are for use in treating said cognitive deficits in subjects who require or are at risk of cognitive deficits associated with CNS disorders. belongs to. In some embodiments, cognitive impairment associated with CNS impairment includes, but is not limited to, age-related cognitive impairment, mild cognitive impairment (MCI), forgetfulness MCI (aMCI), age-related memory impairment (AAMI), Age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), precursor AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, muscular atrophic lateral sclerosis (ALS), cancer Treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, let syndrome, compulsive behavior and substance addiction.

In some embodiments, the present application relates herein in the preparation of a pharmaceutical for the treatment of said cognitive impairment in a subject in need of or at risk of treating a cognitive disorder associated with a CNS disorder. Provided for use of the compounds or compositions described in. In some embodiments, cognitive impairment associated with CNS impairment includes, but is not limited to, age-related cognitive impairment, mild cognitive impairment (MCI), forgetfulness MCI (aMCI), age-related memory impairment (AAMI), Age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), precursor AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, muscular atrophic lateral sclerosis (ALS), cancer Treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, let syndrome, compulsive behavior and substance addiction.

FIG. 1 shows the effect of administration of methyl 3,5-diphenylpyridazine-4-carboxylate on spatial memory retention in 10 aged-impaired (AI) rats in an 8-way radial maze (RAM) test. It is a representation graph. Black bars refer to rats treated with vehicle only; white bars refer to rats treated with different doses of methyl 3,5-diphenylpyridazine-4-carboxylate; shaded bars refer to TB21007 and methyl 3 , 5-Diphenylpyridazine-4-carboxylate refers to rats treated in combination.

FIG. 2 is a graph showing the effect of methyl 3,5-diphenylpyridazine-4-carboxylate (intravenous administration) on the binding of Ro154513 in the hippocampus and cerebellum. Methyl 3,5-diphenylpyridazine-4-carboxylate blocked the binding of Ro154513 in the hippocampus but did not affect the binding of Ro15413 in the cerebellum.

_{FIG. 3 is a graph showing dose-dependent GABA A} α5 receptor occupancy with intravenously administered methyl 3,5-diphenylpyridazine-4-carboxylate, where receptor occupancy is RO15-4513 hippocampal (GABA _{A). GABA A} α5 selective compound L-655,708 _{by ratio of exposure to the cerebral (GABA A} α5 receptor low density region) exposure to RO15-4513 (area with high α5 receptor density) or to define complete occupancy. Measured by using (10 mg / kg, iv).

FIG. 4 is a graph showing the relationship between exposure and occupancy to methyl 3,5-diphenylpyridazine-4-carboxylate in the hippocampus. Methyl 3,5-diphenylpyridazine-4-carboxylate occupies approximately 32% of the GABAAα5 receptor at behaviorally active exposure in aged disabled rats.

FIG. 5 shows ethyl 3-methoxy-7-methyl-9H-benzo [f] imidazo [1,5-a] for spatial memory retention in 10 elderly disabled (AI) rats in an 8-way radial maze (RAM) test. It is a graph showing the effect of [1,2,4] triazolo [4,3-d] [1,4] diazepine-10-carboxylate. FIG. 5 shows ethyl 3-methoxy-7-methyl-9H-benzo [f] imidazo [1,5-a] [1,2,4] for spatial memory retention in 10 elderly (AI) rats in RAM testing. ] Triazolo [4,3-d] [1,4] Diazepine-10-carboxylate has been shown to be effective, where vehicle control is tested three times and in various doses of ethyl 3-methoxy-7-. Methyl-9H-benzo [f] imidazo [1,5-a] [1,2,4] triazolo [4,3-d] [1,4] diazepine-10-carboxylate was tested twice; In FIG. 5, black bars refer to rats treated with vehicle only, white bars are various doses of ethyl 3-methoxy-7-methyl-9H-benzo [f] imidazo [1,5-a] [. 1,2,4] Triazolo [4,3-d] [1,4] Refers to rats treated with diazepine-10-carboxylate.

FIG. 6 shows ethyl 3-methoxy-7-methyl-9H-benzo [f] imidazo [1,5-a] [1,2,4] triazolo [4,3-d] for binding of Ro154513 in the hippocampus and cerebellum. [1,4] It is a graph which shows the effect of diazepine-10-carboxylate (intravenous administration). Ethyl 3-methoxy-7-methyl-9H-benzo [f] imidazole [1,5-a] [1,2,4] triazolo [4,3-d] [1,4] diazepine-10-carboxylate , Blocked the binding of Ro154513 in the hippocampus, but did not affect the binding of Ro15413 in the cerebellum.

FIG. 7 shows the ratio of RO15-4513 hippocampal (GABA _A α5 receptor dense region) exposure to RO15-4513 cerebral (GABA _A α5 receptor low density region) exposure to define complete occupancy. Intravenously administered ethyl 3-methoxy-7-methyl-9H-benzo [f] imidazo [1,5-a] [1,2,4] triazolo [4,3-d] as calculated by ] [1,4] It is a graph showing the _{dose-dependent GABA A} α5 receptor occupancy by diazepine-10-carboxylate.

8 (A)-(C) show 6,6 dimethyl-3- (3-hydroxypropyl) when compared to the vehicle dimethyl sulfoxide (DMSO) using the Maurice water labyrinth behavior task in elderly disabled rats. It is a graph which shows the effect of thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophene-4 (5H) -one. FIG. 8 (A) shows 6,6dimethyl-3- (3-hydroxypropyl) thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophene-4 (5H) -one. It shows the escape latency during training (ie, the average time (in seconds) it took for a rat to find a hidden platform in a water pool) in treated rats and rats treated with vehicle DMSO. FIG. 8 (B) shows 6,6 dimethyl-3- (3-hydroxypropyl) thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophene-4 (5H) -one. The length of time spent in the target cyclic and contralateral annular forms of rats treated with and vehicle DMSO was shown; FIG. 8 (C) shows 6,6 dimethyl-3- (3). -Hydroxypropyl) Thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophene-4 (5H) -on-treated rats and vehicle DMSO-treated rats are targeted cyclic forms. And the number of crossings across the contralateral ring. 8 (A)-(C) show 6,6 dimethyl-3- (3-hydroxypropyl) when compared to the vehicle dimethyl sulfoxide (DMSO) using the Maurice water labyrinth behavior task in elderly disabled rats. It is a graph which shows the effect of thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophene-4 (5H) -one. FIG. 8 (A) shows 6,6dimethyl-3- (3-hydroxypropyl) thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophene-4 (5H) -one. It shows the escape latency during training (ie, the average time (in seconds) it took for a rat to find a hidden platform in a water pool) in treated rats and rats treated with vehicle DMSO. FIG. 8 (B) shows 6,6 dimethyl-3- (3-hydroxypropyl) thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophene-4 (5H) -one. The length of time spent in the target cyclic and contralateral annular forms of rats treated with and vehicle DMSO was shown; FIG. 8 (C) shows 6,6 dimethyl-3- (3). -Hydroxypropyl) Thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophene-4 (5H) -on-treated rats and vehicle DMSO-treated rats have a target cyclic form. And the number of crossings across the contralateral ring. 8 (A)-(C) show 6,6 dimethyl-3- (3-hydroxypropyl) when compared to the vehicle dimethyl sulfoxide (DMSO) using the Maurice water labyrinth behavior task in elderly disabled rats. It is a graph which shows the effect of thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophene-4 (5H) -one. FIG. 8 (A) shows 6,6dimethyl-3- (3-hydroxypropyl) thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophene-4 (5H) -one. It shows the escape latency during training (ie, the average time (in seconds) it took for a rat to find a hidden platform in a water pool) in treated rats and rats treated with vehicle DMSO. FIG. 8 (B) shows 6,6 dimethyl-3- (3-hydroxypropyl) thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophene-4 (5H) -one. The length of time spent in the target cyclic and contralateral annular forms of rats treated with and vehicle DMSO was shown; FIG. 8 (C) shows 6,6 dimethyl-3- (3). -Hydroxypropyl) Thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophene-4 (5H) -on-treated rats and vehicle DMSO-treated rats have a target cyclic form. And the number of crossings across the contralateral ring.

Detailed Description Definitions of the Invention Unless otherwise defined herein, the scientific and terminology used herein shall have meanings commonly understood by one of ordinary skill in the art. In general, the chemistry, cell and tissue culture, molecular biology, cell biology and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, as described herein. Naming and methods used in connection with genetics and protein chemistry and nucleic acid chemistry are well known and commonly used in the art.

Unless otherwise indicated, the methods and methods of the invention are usually in the conventional methods well known in the art, as well as in various general and more specific references cited and discussed throughout this specification. It is done according to the conventional method as described. For example, "Principles of Neuron Science," McGraw-Hill Medical, New York, N.M. Y. (2000); Motulsky, "Intuitive Biostatistics," Oxford University Press, Inc. (1995); Lodish et al., "Molecular Cell Biology, 4th ed.," W. H. Freeman & Co. , New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th ed.," W. H. Freeman & Co. , N. Y. (1999); and Gilbert et al., "Developmental Biology, 6th ed.," Sinauer Associates, Inc. , Sunderland, MA (2000).

The chemical terms used herein are "The McGraw-Hill Education of Chemical Termes," Parker S. et al. , Ed. , McGraw-Hill, San Francisco, C.I. A. It is used according to conventional usage in the art, as illustrated in (1985).

All publications, patents and published patent applications referred to herein are expressly incorporated herein by reference. In the event of a contradiction, the specification, including its specific definition, will prevail.

Throughout the specification, the word "comprise" or variant, eg, "comprises" or "comprising", is an integer (or component) or integer (or component) described. ) Means the inclusion of a group, but is understood to mean the exclusion of any other integer (or component) or group of integers (or components).

The singular forms "a", "an" and "the" include the plural unless the context clearly indicates otherwise.

The term "inclusion" is used to mean "include, but not limited to". "Including" and "including, but not limited to," are used interchangeably.

The term "active substance" refers to a chemical compound (eg, an organic or inorganic compound (eg, including the compounds of the invention), a mixture of chemical compounds), a biological polymer (eg, a nucleic acid, an antibody (eg, one of them). Part and humanized antibodies, including chimeric and human antibodies as well as monoclonal antibodies), proteins or parts thereof, such as peptides, lipids, carbohydrates, or biological materials (eg, bacteria, plants, fungi or animals (particularly). As used herein to refer to an extract from a (mammalian) cell or tissue). The agent includes, for example, an agent known for its structure and an agent not known for its structure. The α5-containing GABA _A receptor agonist activity of such agents may make them suitable as "therapeutic agents" in the methods and compositions of the invention.

"Patient," "subject," or "individual" is used interchangeably and refers to either a human or non-human animal. These terms include mammals (eg, humans, primates, domestic animals (including cows, pigs, etc.), companion animals (eg, dogs, cats, etc.) and rodents (eg, mice and rats)). included.

"Cognitive function" or "cognitive state" means attention, information acquisition, information processing, work memory, short-term memory, long-term memory, forward memory, retrograde memory, memory search, discriminatory learning, decision making, suppression response control. , Attention set shift, delayed enhancement learning, reversal learning, time integration of spontaneous behavior, interest in surrounding environment and self-care, processing speed, reasoning and problem solving, and learning and / / Or refers to any higher-order intellectual brain process or state of memory involved in memory.

In humans, cognitive function is, for example, but not limited to, the Clinical General Impression Change Scale (CIBIC-plus Scale); Mini Mental State Examination (MMSE); Neuropsychological Symptom Assessment (NPI); Clinical Dementia Scale (CDR); Cambridge Neuropsychological Examination Battery (CANTAB); Sandoz Clinical Assessment-Geriatic (SCAG), Buschke Selective Reminding Test (Buschke Selective Reminding Test) (Buschke and 19) Subtest; Logical Memory Subtest; Visual Reproduction Subtest (Wechsler, 1997); Benton Visual Retention Test or Explicit Three-Extreme Forced Selection Method (WMS-R) It can be measured by the explicit 3-alternate memory task) or the MATRICS Consensus Neuropsychological Examination Battery. Folstein et al., J Psychological Res 12: 189-98, (1975); Robbins et al., Dementia 5: 266-81, (1994); Rey, L'examen clinic en psychology, (1964); 12: 168-79, (1999); see Marquis et al., 2002 and Masur et al., 1994. Buchanan, R.M. W. , Keefe, R.M. S. E. , Umbricht, D.I. , Green, M. et al. F. , Laughren, T. et al. , And Marder, S.A. R. (2011), The FDA-NIMH-MATRICS guidelines for clinical trial design of cognitive-enhancing drags: what do we know 5 years later? Schizophr. Bull. See also 37,1209-1217.

In animal model systems, cognitive function includes the use of the Maurice Water Maze (MWM), Burns Circular Maze, Elevated Radial Maze, T-Maze, or any other maze in which the animal uses spatial information. It can be measured by various known conventional methods. Cognitive function can be assessed by reversal learning, extradimensional set shifting, conditioned discriminatory learning, and evaluation of reward expectations. Other tests known in the art can also be used to evaluate cognitive functions such as novel object recognition tasks and odor recognition tasks.

Cognitive function can be imaging technology (eg, positron emission tomography (PET), functional magnetic resonance imaging (fMRI), single photon emission computed tomography (SPECT), or any other measurement of brain function. It can also be measured using imaging technology). In animals, cognitive function can also be measured by electrophysiological techniques.

"Promotion" of cognitive function means that impaired cognitive function affects impaired cognitive function in a manner that closely resembles the function of a normal, unimpaired subject. Cognitive function can be promoted to any detectable extent, but in humans, the impaired subject is preferably an intact normal subject or an intact normal age subject. Encouraged enough to be able to carry out daily activities of normal life at a proficiency level as close as possible to.

In some cases, "promotion" of cognitive function in a subject affected by age-related cognition means that the impaired cognitive function is not impaired, the function of a normal same-aged subject or a young adult subject. It refers to affecting impaired cognitive function, much like the function of. The cognitive function of the subject can be enhanced to any detectable extent, but in humans, the impaired subject is preferably an unimpaired normal or juvenile adult subject or impaired. It is sufficiently promoted to be able to perform daily activities of normal life at a proficiency level as close as possible to a non-normal age subject.

"Preservation" of cognitive function means that normal or impaired cognitive function does not decline, or that it does not decline below the cognitive function observed in the subject at the time of initial presentation or diagnosis, or. It refers to affecting normal or impaired cognitive function so that such decline is delayed.

"Improvement" of cognitive function includes promotion of cognitive function and / or preservation of cognitive function in the subject.

"Cognitive impairment" refers to cognitive function in a subject that is not as robust as expected cognitive function in a normal, intact subject. In some cases, cognitive function is reduced by about 5%, about 10%, about 30%, or more, compared to the cognitive function expected in a normal subject unimpaired. In some cases, "cognitive impairment" in a subject affected by age-related cognitive impairment is the cognitive function or juvenile adult subject expected in an intact, normal age subject (ie, a cognitive test). Refers to cognitive function in a subject that is not as robust as the function of a subject) who has an average score for a given age.

"Aging-related cognitive impairment" refers to cognitive impairment in older subjects, where the cognitive function of those subjects is the cognitive function expected in normal same-aged subjects or young adults. Not as robust as expected cognitive function in the subject. In some cases, cognitive function is reduced by about 5%, about 10%, about 30%, or more, compared to the cognitive function expected in normal same-aged subjects. In some cases, cognitive function is as much as expected cognitive function in normal same-aged subjects, but about 5%, about 10%, and about 30 compared to cognitive function expected in young adult subjects. %, About 50% or more. Age-related impaired cognitive function is associated with mild cognitive impairment (MCI) (including amnestic MCI and non-amnestic MCI), age-related memory impairment (AAMI) and age-related cognitive decline (ARCD). obtain.

"Cognitive impairment" in AD-related or AD-related or in AD is in subjects who are not as robust as expected cognitive function in subjects who have not been diagnosed with AD using conventional methods and criteria. Refers to cognitive function.

"Mild cognitive impairment" or "MCI" refers to a condition characterized by isolated memory deficits without other cognitive abnormalities and relatively normal functional abilities. One set of criteria for clinically characterizing MCI is as follows: (1) Memory complaints (reported by the patient, informant or physician), (2) Normal activities of daily living (ADL), ( 3) Normal total cognitive function, (4) Abnormal memory for age (defined as scoring 1.5 standard deviations below mean for a given age) and (5) Dementia index (DSM- Clarifies that there is no such thing as defined by the IV guidelines). Petersen et al., Srch. Neurol. 56: 303-308 (1999); Petersen, “Mild cognitive impairment: Aging to Alzheimer's Disease.” Oxford University Press, N.M. Y. (2003). Agnosia in subjects with MCI can involve any cognitive or mental process, including memory, language, association, attention, perception, problem-solving, executive function and visuospatial skills. For example, Winbald et al., J. Mol. Intern. Med. 256: 240-240, 2004; Meguro, Acta. Neurol. Taiwan. 15: 55-57, 2008; Ellison et al., CNS Spector. 13: 66-72, 2008, Petersen, Semin. Neurol. See 27: 22-31, 2007. MCI is further subdivided into amnestic MCI (aMCI) and non-amnestic MCI, which are particularly characterized by memory dysfunction (or loss thereof). MCI is defined as aMCI if memory is found to be impaired, taking into account the subject's age and level of education. On the other hand, if the subject's memory turns out to be intact with respect to age and education, but other non-memory cognitive areas (eg, language, executive function or visuospatial skills) are impaired, MCI , Defined as non-amnestic MCI. Both aMCI and non-amnestic MCI can be further subdivided into single-region MCI or multi-region MCI. aMCI-single region refers to a condition in which memory is not impaired but other cognitive regions are impaired. aMCI-Multiple regions refer to a medical condition in which memory and at least one other cognitive region are impaired. Non-amnestic MCI is a single region or multiple regions, depending on whether more than one non-memory cognitive region is impaired. For example, Peterson and Negash, CNS Specter. See 13: 45-53, 2008.

Diagnosis of MCI is usually a well-established neuropsychological test (Mini-Mental State Examination (MMSE), Cambridge Neuropsychological Test Battery (CANTAB)) and individual tests (eg, Ray Auditory Language Learning Test (eg, Ray Auditory Language Learning Test). AVLT), a cognitive impairment that can be acquired by using the Wexler Memory Test Revised Edition (WMS-R) Logical Memory Subtest and the New York Universality (NYU) Paragraph Recollection Test (including the Paragraph Recall Test). Requires objective evaluation. Folstein et al., J Psychitric Res 12: 189-98 (1975); Robbins et al., Dementia 5: 266-81 (1994); Kruger et al., J. )checking.

"Age-related memory impairment (AAMI)" refers to a decline in memory due to aging. A patient may be considered to have AAMI if the patient is at least 50 years old and meets all of the following criteria: a) the patient is aware of diminished memory capacity, b) the patient is , Poor standard memory test performance compared to young adults, c) Excludes all other obvious causes of memory loss except normal aging (in other words, memory loss is another cause) (For example, recent heart attacks or head injuries, depression, adverse reactions to drug therapy, Alzheimer's disease, etc.) cannot be blamed).

"Age-related cognitive decline (ARCD)" refers to a decline in memory and cognitive ability that is a normal result of aging in humans (eg, Crik & Salthouse, 1992). This is true for virtually all mammalian species. Age-related memory deficits refer to older people who have objective memory loss compared to younger people but have normal cognitive function compared to older people (Crook et al., 1986). Age-consistent memory declines are these normal developmental changes (Crook, 1993; Larrabee, 1996), not pathophysiological (Smith et al., 1991), and rarely progress to overt dementia. It is a less derogatory expression that emphasizes that (Youngjon & Crook, 1993). DSM-IV (1994) systematized the diagnostic classification of ARCD.

"Dementia" refers to a condition characterized by severe agnosia that interferes with normal activities of daily living. Subjects with dementia also exhibit other symptoms such as impaired judgment, personality changes, disorientation, confusion, behavioral changes, speech difficulties and movement disorders. Dementia includes various types, such as Alzheimer's disease (AD), vascular dementia, Lewy body dementia and corticobasal degeneration.

Alzheimer's disease (AD) is characterized by its early memory deficiency. Late symptoms include impaired judgment, disorientation, confusion, behavioral changes, speech difficulties and movement disorders. Histologically, AD is characterized by beta-amyloid plaques and concentrates of tau protein.

Vascular dementia is caused by a stroke. Symptoms overlap with those of AD, but the focus is not on memory impairment.

Lewy body dementia is characterized by abnormal deposition of alpha-synuclein that forms inside neurons in the brain. Cognitive deficits, including memory and judgment dysfunction and behavioral changes, may resemble AD.

Corticobasal degeneration is characterized by gliosis, neuronal loss, superficial spongiform degeneration in the frontal cortex and / or frontal temporal lobe, and pick bodies. Symptoms include personality and behavioral changes, including poor social skills and verbal expression / comprehension.

"Post-traumatic stress disorder (PTSD)" is characterized by an acute or delayed response to a catastrophe, characterized by re-experience of trauma, avoidance of stimuli associated with mental numbness or trauma, and increased arousal. Refers to anxiety disorders. Re-experience of the phenomenon includes intrusive memory, flashbacks, nightmares and psychological or physiological anguish in response to traumatic reminders. Such reactions can lead to anxiety and have significant chronic and acute effects on the patient's quality of life as well as physical and emotional health. PTSD is also associated with impaired cognitive ability, with older individuals with PTSD having a greater decline in cognitive ability than control patients.

"Schizophrenia" is a positive symptom, eg, a negative symptom characterized by abnormal or distorted psychotic representation (eg, hallucinations, delusions), diminished motivation and diminished adaptive goal-oriented behavior (eg,). , Loss of pleasure, flattening of emotions, loss of motivation) and chronic debilitating disorders characterized by a series of psychopathologies including cognitive impairment. Although abnormalities in the brain have been proposed to form the basis of widespread psychopathology in schizophrenia, currently available antipsychotics are often ineffective in treating cognitive impairment in patients.

"Bipolar disorder" or "BP" or "manic-depressive disorder" or "manic-depressive disorder" can be characterized by significant mood changes, including periods of depression and periods of euphoric manic disorder. / Refers to mood disorders. BP can be diagnosed by a skilled physician based on personal and medical history, interviews and physical examinations. The term "manic" or "manic period" or other variant refers to the period during which an individual exhibits some or all of the following characteristics: at the level of competitiveness, fast-talking, activity and agitation. Elevation, as well as a feeling of bloated self-esteem, euphoria, misjudgment, insomnia, impaired concentration and aggression.

"Amyotrophic lateral sclerosis," also known as ALS, is a progressive, fatal neurodegenerative disease characterized by degeneration of motor neurons, which are nerve cells in the central nervous system that control voluntary movements of muscles. Point to that. ALS is also characterized by neurodegeneration, memory deficits in the entorhinal cortex and hippocampus, and hyperexcitatory neurons in various brain regions, such as the cortex.

"Cognitive impairment associated with cancer treatment" refers to cognitive impairment that develops in a subject being treated with cancer treatment such as chemotherapy and radiation. Cytotoxic and other adverse side effects of cancer treatment on the brain result in cognitive impairment in functions such as memory, learning and attention.

Parkinson's disease (PD) is a neuropathy characterized by decreased voluntary movement. Patients suffering from this have less motor activity and slower voluntary movements than normal individuals. Patients have a characteristic "mask-like" facial appearance, a tendency to rush while walking, a crooked posture and systemic weakness of the muscles. There is a typical "leadpipe-like" rigidity of passive motion. Another important feature of the disease is limb tremor, which occurs at rest and decreases during exercise.

"Autism" as used herein is an autism spectrum characterized by neurogenesis disorders leading to impaired social interaction and communication due to restricted and repetitive behaviors. Refers to an obstacle. "Autism spectrum disorders" are developmental disorders including autism; Asperger's syndrome; pervasive developmental disorders (PDD-NOS or atypical autism); Rett syndrome; and childhood disintegrative disorders. Refers to a group.

Mental retardation is a general disorder characterized by severely impaired cognitive function and adaptive behavioral deficiencies. Mental retardation is often defined as an IQ score of less than 70. Congenital causes are many root causes of mental retardation. Neuronal communication dysfunction is also thought to be one of the root causes of mental retardation (Myrrh van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214). ..

In some cases, mental retardation includes Down's Syndrome, Velocariofacial Syndrome, Fetal Alcohol Syndrome, Vulnerable X Syndrome, Kleinfelder Syndrome, Neurofibromatosis, Congenital Hypothyroidism, Williams Syndrome, Phenylketone. Includes Urinology (PKU), Smith-Remli-Opitz Syndrome, Prader Willy Syndrome, Ferran McDermid Syndrome, Mowat Wilson Syndrome, Hair-related Diseases, Law Syndrome and Siderium Type X-Chain Mental Retardation Not limited to. Down's syndrome is a disorder that includes a combination of some degree of mental retardation, characteristic facial features, and often heart defects, many infections, visual and hearing problems, and birth defects, including other health problems. Fragile X syndrome is a common form of hereditary mental retardation that occurs in 1 in 4,000 men and 1 in 8,000 women. The syndrome is also characterized by stunted growth, hyperactivity, attention deficit disorder and autism-like behavior. There is no effective treatment for Fragile X Syndrome.

Obsessive-compulsive disorder (“OCD”) is most commonly an intrusive, repetitive and unnecessary thought (compulsion) that causes an individual to feel compelled to act (forced), compulsive and mental behavior. It is a mental state characterized by. Current epidemiological data indicate that OCD is the fourth most common mental illness in the United States. Several studies suggest that the prevalence of OCD is 1-3 percent, but the clinically recognized prevalence of OCD is much lower, so many individuals with the disorder It is suggested that may not have been diagnosed. Patients with OCD should be a psychologist, psychiatrist or psychiatrist according to the diagnostic criteria of the Digital and Statistical Manual of Mental Disorders, 4th edition text revision (DSM-IV-TR) (2000), including the features of obsessive-compulsive and compulsive. Often diagnosed by scholars.

Substance addiction (eg, drug addiction, alcohol addiction) is a mental disorder. This addiction is not instantly triggered when exposed to a substance of abuse. Rather, this addiction requires the adaptation of multiple complex neurons that occur over time, ranging from hours to days to months (Kauer JA Nat. Rev. Neurosci. 2007). , 8,844-858). The path to addiction is usually from the voluntary use of one or more regulatory substances (eg, narcotics, barbiturates, methamphetamine, alcohol, nicotine and any of a variety of other such regulatory substances). It starts. Sustained use of these regulators over a long period of time impairs the voluntary ability to refrain from those regulators due to the effects of long-term use on brain function and hence behavioral effects. .. Therefore, substance addiction is usually characterized by obsessive-compulsive substance cravings, exploration and use that persist despite negative consequences. That desire can correspond to the underlying neurobiological changes in the patient, which must probably be addressed in a meaningful way if recovery is to be achieved. Material addiction is often also characterized by life-threatening withdrawal symptoms (eg, alcohol, barbiturates) for some substances and, in other cases, substantial morbidity (nausea, vomiting, fever). Can include dizziness and heavy sweating), distress, and diminished ability to recover. For example, alcoholism, also known as alcoholism, is one such substance addiction. Alcoholism is primarily characterized by four symptoms, including desire, loss of control, physical dependence and tolerance. These symptoms may also characterize addiction to other regulatory substances. The desire for alcohol and other regulated substances is often as strong as the desire for food or water. Therefore, alcoholics may continue to drink despite significant family, health and / or legal side effects.

"Treatment" of a medical condition or patient refers to the step of obtaining beneficial or desired results (including clinical results). Beneficial or desired clinical outcomes include prevention of the disease or disorder or delay in its progression, or cognitive impairment associated with CNS impairment (eg, age-related cognitive impairment, mild cognitive impairment (MCI), forgetfulness MCI). aMCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), precursor AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, muscle One of atrophic lateral sclerosis (ALS), cognitive impairment associated with cancer treatment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, let syndrome, compulsive behavior and substance addiction) Or beyond, alleviation, recovery, or delay in progression thereof, but is not limited to these. In some embodiments, treatment involves prevention of CNS disorders (eg, as described herein) or delay in their progression. In certain embodiments, treatment comprises alleviating, ameliorating or delaying the progression of one or more symptoms associated with a CNS disorder. In certain embodiments, the symptom being treated is cognitive impairment or agnosia. Treatment of age-related cognitive impairment further includes delayed conversion of age-related cognitive impairment (including but not limited to MCI, ARCD and AAMI) to dementia (eg, AD).

"Treatment of cognitive impairment" means that the performance of one or more subjects with cognitive impairment in a cognitive test is improved to any detectable extent or is prevented from further decline. In addition, it refers to performing a step of improving cognitive function in the subject. Preferably, the cognitive function of the subject closely resembles that of a normal subject that has not been impaired after treatment of the cognitive impairment. Treatment of cognitive impairment in humans can improve cognitive function to any detectable extent, but preferably impaired subjects live normally at the same level of proficiency as normal, unimpaired subjects. It is improved enough to make it possible to carry out daily activities. In some cases, "treating cognitive impairment" means improving or further reducing performance in a cognitive test of one or more subjects with cognitive impairment to any detectable extent. Refers to the step of improving cognitive function in the subject so as to be prevented. Preferably, the cognitive function of the subject closely resembles that of a normal subject that has not been impaired after treatment of the cognitive impairment. In some cases, "treating cognitive impairment" in a subject affected by age-related cognitive impairment means that the subject's cognitive function is not impaired after treatment of the cognitive impairment and is of normal age. Refers to the step of improving cognitive function in a subject so as to closely resemble the function of the subject or the function of a young adult subject.

"Administration" of a substance, compound or agonist to a subject or "administration of a substance, compound or agonist" to a subject can be performed using one of a variety of methods known to those of skill in the art. .. For example, the compound or agent may be intravenously, arterial, intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, into the eyeball, sublingually, orally (by oral ingestion). It can be administered intranasally (by inhalation), into the spinal cord, into the brain, and transdermally (by absorption, eg, through a skin duct). The compound or agent is appropriately introduced by a refillable or biodegradable polymer device or other device, such as a patch and pump, or a formulation that results in sustained, sustained or controlled release of the compound or agent. Can be done. Also, administration can be performed, for example, once, multiple times and / or over a long period of one or more. In some embodiments, administration comprises both direct administration (including self-administration) and indirect administration (including the act of prescribing a drug). For example, as used herein, a doctor instructing a patient to self-administer a drug, or a doctor instructing another person to administer a drug, and / or a prescription for a patient. The physician providing the drug is administering the drug to the patient.

A suitable method of administering a substance, compound or agent to a subject is, for example, the age of the subject, whether the subject at the time of administration is active or inactive, or cognitive impairment to the subject at the time of administration. It may also depend on the presence or absence, the degree of dysfunction, and the chemical and biological properties of the compound or agent (eg, solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, the compound or agent is administered orally, eg, by oral ingestion of the subject, or intravenously, eg, by injection into the subject. In some embodiments, the compound or agent that is orally administered is a sustained release or sustained release formulation, or is administered using a device for such sustained release or sustained release.

As used herein, ".alpha.5-containing GABA _A receptor agonist", ".alpha.5-containing GABA A _R agonist" or "GABA _A .alpha.5 receptor agonist" and other variations as used herein is, .alpha.5 compounds to improve the function of containing GABA _a receptor (GABA _a R), i.e., GABA-gated Cl ^- refers to current compounds that increase. In some embodiments, .alpha.5-containing GABA A _R agonists, as used herein, refers to a positive allosteric modulators that enhance the activity of GABA. The α5 containing GABA _A receptor agonists suitable for use in the present invention, all of the formulas described herein α5 containing GABA _A receptor agonists and specific α5 containing GABA _A receptor agonist, as well as their Includes hydrates, solvates, polymorphs, salts (eg, pharmaceutically acceptable salts), isomers (eg, steric isomers, E / Z isomers and homomorphs) and combinations.

"Anti-psychiatric drugs", "anti-psychiatric agents", "anti-psychiatric drugs" or "anti-psychiatric compounds" are (1) typical anti-psychiatric agents or atypical anti-psychiatric agents; (2) dopamine agonists, glutamate agonists. , NMDA Receptor Positive Allosteric Modulator, Glycin Reuptake Inhibitor, Glutamic Acid Reuptake Inhibitor, Metabolized Glutamic Acid Receptor (mGluR) Agonist or Positive Allosteric Modulator (PAM) (eg, mGluR2 / 3 Agonist or PAM), Glutamic Acid Receptor glur5 Positive Allosteric modulator (PAM), M1 muscarinic acetylcholine receptor (mAChR) positive allosteric modulator (PAM), histamine H3 receptor antagonist, AMPA / quinic acid receptor antagonist, ampakines (CX-516), glutathione prodrug, noradrenaline agonist , Serotonin receptor modulator, choline agonist, cannabinoid CB1 antagonist, neurokinin 3 antagonist, neurotensin agonist, MAOB inhibitor, PDE10 inhibitor, nNOS inhibitor (inhibits), neurosteroid and neuronutrient factor, alpha-7 agonist or Positive Allosteric Modulator (PAM) PAM, agonist selected from serotonin 2C agonists; and / or (3) useful in the treatment of one or more signs or symptoms of schizophrenia or bipolar disorder (particularly manic disease) Refers to an agonist.

"Typical antipsychotics", when used herein, are conventional antipsychotics that have antipsychotic effects, as well as exercise-related adverse effects associated with disorders of the dopamine system of the substantia nigra striatum. Point to that. These extrapyramidal side effects (EPS) include parkinsonism, inability to sit, tardive dyskinesia and dystonia. Baldessarini and Tarazi in Goodman & Gilman's The Pharmacological Basics of Therapeutics 10 Edition, 2001, pp. See 485-520.

"Atypical antipsychotics" as used herein refer to antipsychotics that produce antipsychotic effects with little or no EPS, such as alipiprazole, acenapine, clozapine, etc. Includes, but is not limited to, iloperidone, olanzapine, lulacidone, paliperidone, quetiapine, risperidone and ziprasidone. "Atypical" antipsychotics differ in their pharmacological profile from traditional antipsychotics. Conventional antipsychotic drugs, mainly characterized by blockade of D ₂ dopamine receptor, but atypical antipsychotics, the degree antagonistic action and various to multiple receptors including 5HT _a and 5HT _c serotonin receptor Shows receptor affinity. Atypical antipsychotic drugs are usually also referred to as serotonin / dopamine antagonist, which is higher affinity for 5HT ₂ receptors than D ₂ receptors, "atypical" activity or "second generation" anti-psychotic drugs anti It reflects the influential hypothesis that it forms the basis of psychotic drugs. However, atypical antipsychotics include weight gain, diabetes (eg, type II diabetes), hyperlipidemia, prolonged QTc intervals, myocarditis, sexual side effects, extrapyramidal side effects and cataracts. Often presents with unrestricted side effects. Therefore, atypical antipsychotics are not in the uniform class given the differences in both the mitigation of clinical symptoms and the potential to induce side effects such as those listed above. Moreover, the usual side effects of atypical antipsychotics as described above often limit the dose of antipsychotics available for these agents.

Memantine is chemically known as 3,5-dimethyladamantane-1-amine or 3,5-dimethyltricyclo [3.3.1.1 ^3,7 ] decane-1-amine and is moderate. It is an uncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist with affinity. Trademark names for memantine include Axura® and Akatinol® (Merz), Namenda® (Forest Laboratories), Ebiza® and Abixa® (Lundbeck) and Memax®. Trademark) (Unipharm). Memantine has been approved in the United States for the treatment of moderate to severe Alzheimer's disease (AD) at doses of up to 28 mg / day. Derivatives or analogs of memantine, including compounds structurally or chemically similar to memantine, are also useful in the present invention. As such Memantin derivatives or analogs, U.S. Pat. Nos. 3,391,142; 4,122,193; 4,273,774 and 5,061,703; U.S. Pat. Publication US2004087658, US20050113458, US20060205822, US2009081259, US20090124659 and US20100227852; European Patent Application Publication EP22608389A2; European Patent EP1682109B1; and PCT Application Publication WO200507779 (all of which are incorporated herein by reference). Examples include, but are not limited to, compounds. As used in the present invention, memantine includes memantine and its derivatives and analogs, as well as hydrates, polymorphs, prodrugs, salts and solvates thereof. As used herein, memantine also includes compositions containing memantine or its derivatives or analogs or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof. Here, the composition further comprises, as needed, at least one additional therapeutic agent (eg, a therapeutic agent useful in the treatment of CNS disorders or cognitive disorders associated therewith). In some embodiments, the memantine composition suitable for use in the present invention comprises memantine and a second therapeutic agent, donepezil (trade name Alicept).

"Acetylcholinesterase inhibitor" or "AChE-I", when used herein, are primarily brain synapses or neuromuscular junctions by inhibiting the ability of cholinesterase enzymes to degrade the neurotransmitter acetylcholine. Refers to an agent that increases the concentration of acetylcholine in the body and prolongs its duration. Suitable AChE-Is for use in the present application are, for example, (i) reversible non-competitive or reversible competitive inhibitors, (ii) irreversible inhibitors, and (iii) quasi-irreversible. Can include subcategories of inhibitors.

The term "co-administration" as used herein means an α5-containing GABA _A receptor agonist (eg, an α5-containing GABA _A receptor positive allosteric modulator) and a second therapeutic agent (eg, an antipsychotic, memantine or AChE-I) or pharmaceutically acceptable salts, hydrates, solvates or polymorphs thereof do not exceed about 10 minutes in some embodiments at time intervals not exceeding about 15 minutes. It means that it is administered at time intervals. When the drug is co-administered, an α5-containing GABA _A receptor agonist (eg, α5-containing GABA _A receptor positive allosteric modulator) and a second therapeutic agent (eg, antipsychotic, memantine or AChE-I) or salts thereof. , Hydrate, solvate or polyform, the same dosage form (eg, α5-containing GABA _A receptor agonist (eg, α5-containing GABA _A receptor positive allosteric modulator) and a second therapeutic agent (eg, antipsychotics, etc.) It may be included in a unit dosage form containing both memantine or AChE-I) or in a separate dosage form (eg, α5-containing GABA _A receptor agonist (eg, α5-containing GABA _A receptor positive). Allosteric modulators) or salts thereof, hydrates, solvates or polymorphisms are included in one dosage form and a second therapeutic agent (eg, antipsychotic, memantine or AChE-I) or salts thereof, water. Japanese, solvated or polyforms are included in other dosage forms).

The term "continuous dosing", as used herein, refers to an α5-containing GABA _A receptor agonist (eg, an α5-containing GABA _A receptor positive allosteric modulator) and a second therapeutic agent (eg, an antipsychotic, memantine or or AChE-I) or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs at time intervals greater than about 15 minutes, in some embodiments greater than about 1 hour or It means that it is administered at time intervals of up to 12 to 24 hours. Either an α5-containing GABA _A receptor agonist (eg, an α5-containing GABA _A receptor positive allosteric modulator) or a second therapeutic agent (eg, an antipsychotic, memantine or AChE-I) may be administered first. Α5-containing GABA _A receptor agonists for continuous administration (eg, α5-containing GABA _A receptor positive allosteric modulators) and second therapeutic agents (eg, antipsychotics, memantine or AChE-I) or salts and hydrates thereof. , Receptors or polyforms can be included in separate dosage forms, optionally in the same container or packaging.

A "therapeutic effective amount" of a drug or agent, when administered to a subject, provides the intended therapeutic effect, eg, improvement of cognitive function, in the subject, eg, a patient with cognitive impairment associated with a CNS disorder. The amount of drug or agent it has. The complete therapeutic effect is not always manifested by a single dose, but may only appear after a series of doses. Therefore, the therapeutically effective amount may be administered once or more times. The exact effective amount required for a subject is, for example, subject size, health and age, cognitive impairment or other symptoms of CNS impairment (eg, age-related cognitive impairment, mild cognitive impairment (MCI), dementia). , Alzheimer's disease (AD), precursor AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolarity, ALS, cognitive impairment associated with cancer treatment, mental retardation, Parkinson's disease (PD), autism spectrum disorder , Vulnerability X disorder, Let's syndrome, compulsive behavior and substance addiction), as well as the therapeutic agent or combination of therapeutic agents selected for administration, and the mode of administration. One of ordinary skill in the art can easily determine the effective amount for a given situation by routine experimentation.

The compounds of the invention also include prodrugs, analogs or derivatives. The term "prodrug" is recognized in the art, it is intended to encompass a compound or agent is converted into α5 containing GABA A _R positive allosteric modulators under physiological conditions. The usual method for producing a prodrug is to select a moiety that is hydrolyzed or metabolized under physiological conditions to provide the desired compound or agent. In other embodiments, the prodrug is _{converted to a GABA A} α5 receptor positive allosteric modulator by enzymatic activity of the host animal.

"Analog" is used herein to refer to a compound that is functionally similar to another chemical entity but does not share the same chemical structure. For example, analogs are sufficiently similar to the basic or parent compound to the extent that they can be used in place of the basic compound in therapeutic applications, despite minor structural differences.

"Derivative" is used herein to refer to the chemical modification of a compound. Chemical modifications of the compound may include, for example, substitution of hydrogen with an alkyl group, an acyl group or an amino group. There can be many other modifications.

The term "aliphatic" as used herein refers to linear or branched alkyl, alkenyl or alkynyl. It is understood that embodiments of alkenyl or alkynyl require at least two carbon atoms in the aliphatic chain. Aliphatic groups usually contain 1 (or 2) to 12 carbons, eg, 1 (or 2) to 4 carbons.

The term "aryl", as used herein, refers to a monocyclic or bicyclic aromatic ring system. As used herein, aryl includes (C6-C12) -aryl-. For example, as used herein, aryl can be a C6-C10 monocyclic or C8-C12 bicyclic carbocyclic aromatic ring system. In some embodiments, the aryl, as used herein, can be (C6-C10) -aryl-. Phenyl (or Ph) is an example of a monocyclic aromatic ring system. Bicyclic aromatic ring systems include systems in which both rings are aromatic, such as naphthyl, and systems in which only one of the two rings is aromatic, such as tetralin.

The term "heterocyclic", as used herein, chemically refers to 1 to 4 heteroatoms or heteroatom groups selected from O, N, NH, S, SO or SO _2. It refers to a monocyclic or bicyclic non-aromatic ring system having a stable arrangement. As used herein, the heterocyclic formula is a 3- to 12-membered heteroatom having 1 to 4 heteroatoms independently selected from O, N, NH, S, SO or SO _2. Heterocyclyl-is included. For example, as used herein, a heterocyclic formula chemically stabilizes 1 to 4 heteroatoms or heteroatom groups selected from O, N, NH, S, SO or SO _2. It can be a 3- to 10-membered monocyclic or 8- to 12-membered bicyclic non-aromatic ring system with a similar arrangement. In some embodiments, when used herein, the heterocyclic formula contains 1 to 4 heteroatoms selected independently of _{O, N, NH, S, SO or SO 2.} It can be a heterocyclyl with 3 to 10 members. In embodiments of a "heterocyclyl" bicyclic non-aromatic ring system, one or both rings may comprise the heteroatom or heteroatom group. In another bicyclic "heterocyclyl" embodiment, one of those two rings can be aromatic. Still in another embodiment of the heterocyclic ring system, the non-aromatic heterocyclic ring can be condensed into an aromatic carbocyclic compound, if desired.

Examples of heterocyclic rings are 3-1H-benzimidazol-2-one, 3- (1-alkyl) -benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl. , 3-Tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropipe Radinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2 -Piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinoli Nyl, benzothiorane, benzodithian and 1,3-dihydro-imidazol-2-one.

The term "heteroaryl", as used herein, simply has one to four heteroatoms or heteroatom groups selected from O, N, NH or S in a chemically stable configuration. Refers to a cyclic or bicyclic aromatic ring system. As used herein, heteroaryls include 5- to 12-membered heteroaryls having 1 to 4 heteroatoms independently selected from O, N, NH or S. .. In some embodiments, when used herein, a heteroaryl is a 5- to 10-membered member having 1 to 4 heteroatoms selected independently of O, N, NH or S. Can be heteroaryl. For example, as used herein, a heteroaryl is chemically stable with one to four heteroatoms or heteroatom groups selected from O, N, NH or S on one or both rings. It can be a 5- to 10-membered monocyclic or 8- to 12-membered bicyclic aromatic ring system with a similar arrangement. In embodiments of such bicyclic aromatic ring systems of "heteroaryl".
-Both rings are aromatic; and-one or both rings may contain the heteroatom or heteroatom group.

Examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzoimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-Oxazolyl, 5-oxazolyl, N-pyrrolid, 2-pyrrolid, 3-pyrrolid, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridadinyl (eg, 3-pyridazinyl). Pyridadinyl), 2-thiazolinyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (eg, 5-tetrazolyl), triazolyl (eg, 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuryl, benzothiophenyl. , Indrill (eg 2-indrill), pyrazolyl (eg 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3 -Triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, prynyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (eg 2-quinolinyl, 3-quinolinyl) , 4-quinolinyl) and isoquinolinyl (eg, 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl).

The term "cycloalkyl or cycloalkenyl" refers to a non-aromatic, monocyclic carbocyclic or fused or crosslinked bicyclic carbocyclic. For example, as used herein, cycloalkyl or cycloalkenyl is a non-aromatic, C3-C10 monocyclic carbocyclic system or condensed or crosslinked C8-C12 bicyclic carbocyclic ring system. obtain. The cycloalkenyl ring has one or more unsaturated units. Preferred cycloalkyl or cycloalkenyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, adamantyl and decalynyl.

As used herein, a carbon atom manifestation can have the integers shown and any intervening integers. For example, the number of carbon atoms in the (C1-C4) -alkyl group is 1, 2, 3 or 4. It should be understood that these manifestations refer to the total number of atoms in the appropriate group. For example, in (C3-C10) -heterocyclyl, the total number of carbon atoms to heteroatoms is 3 (as in aziridine), 4, 5, 6 (as in morpholine), 7, 8, 9 or 10. ..

"Pharmaceutically acceptable salt" is used herein to refer to an agent or compound according to the invention in the form of a therapeutically active, non-toxic base and acid salt of the compound according to the invention. Used in the specification. The form of the acid addition salt of the compound, which is present as a base in its free form, is such that the form of the free base is an appropriate acid, such as an inorganic acid, such as a hydrohalogen acid (eg, hydrochloric acid or hydrobromic acid), sulfuric acid. , Nitrate, phosphoric acid, etc .; or organic acids such as acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvate, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartrate acid, citric acid, methanesulfonic acid, It can be obtained by treatment with ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclic acid, salicylic acid, p-aminosalicylic acid, pamoic acid and the like. See, for example, WO01 / 062726.

A compound containing an acidic proton can be converted into a therapeutically active, non-toxic base addition salt form of the compound, eg, a metal salt or an amine salt, by treatment with the appropriate organic and inorganic bases. Suitable base salt forms include, for example, ammonium salts, alkali metal salts and alkaline earth metal salts such as lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts and the like. Salts include, for example, N-methyl-D-glucamine salts, hydrabamine salts, and salts with amino acids (eg, arginine, lysine, etc.). Conversely, the salt form can be converted to the free form by treatment with a suitable base or acid.

Compounds and salts thereof may be in the form of solvates within the scope of the present invention. Examples of such solvates include hydrates, alcoholates and the like. See, for example, WO01 / 062726.

As used herein, the term "hydrate" refers to a combination of water and a compound, wherein the water retains its molecular state as water and is of a substrate compound. Absorbed, adsorbed, or contained within the crystal lattice.

As used herein, the term "polymorph" refers to different crystalline forms of the same compound and other solid state molecular forms (including pseudopolymorphs), such as hydrates of the same compound (including pseudopolymorphs). For example, it refers to a binding water (in which bound water is present in the crystal structure) and a solvate (for example, a binding solvent other than water). Different crystalline polymorphs have different crystal structures due to the different filling of molecules in their lattices. This results in different crystal symmetry and / or unit cell parameters, which directly affect physical properties such as the characteristics of X-ray diffraction of the crystal or powder. For example, different polymorphs generally diffract at different angle sets and give different values for their intensities. Therefore, by using powder X-ray diffraction, the morphology of solids containing different polymorphs or more than one polymorph can be identified in a reproducible and reliable manner. The crystalline polymorphic form is of interest to the pharmaceutical industry and, in particular, those involved in the development of suitable dosage forms. If the polymorphic form is not kept constant in clinical or stability studies, the exact dosage form used or studied may not be comparable by lot. Because when a compound is used in clinical research or commercial, the impurities present can result in unwanted toxicological effects, thus producing the compound in high purity with the polymorphic form of choice. It is also desirable to have the process of. Certain polymorphic forms may exhibit improved thermodynamic stability or may be more easily produced in large quantities with high purity and are therefore more suitable for inclusion in pharmaceutical formulations. Certain polymorphs may exhibit other beneficial physical properties (eg, lack of hygroscopic tendencies, improved solubility, and improved dissolution rates due to different lattice energies).

The present application contemplates all isomers of compounds of formulas I-IV. As used herein, "isomers" include optical isomers (eg, stereoisomers such as enantiomers and diastereoisomers), Z (zusammen) or E (entgegen) isomers, and. Includes tautomers. Many of the compounds useful in the methods and compositions of the invention have at least one asymmetric center in their structure. This asymmetric center may exist in an R or S arrangement, and the notation of R and S is described in Pure Appl. Chem. (1976), 45, 11-30, used according to the rules. The invention also relates to all stereoisomers (eg, mirror and diastereoisomers of the compound) or mixtures thereof, including all possible mixtures of stereoisomers. See, for example, WO01 / 062726. In addition, certain compounds containing alkenyl groups can be present as Z (zusammen) or E (entgegen) isomers. In each case, the invention comprises a mixture of both and separate individual isomers. Multiple substituents on the piperidinyl or azepanyl ring may be located in a cis or trans relationship with each other with respect to the plane of the piperidinyl or azepanyl ring. Some of these compounds can also exist as tautomers. Such forms are not expressly shown in the formulas described herein, but are intended to be included within the scope of the invention. References to a compound with respect to the methods and compositions of the invention are intended to include each possible isomer of the compound and the compound as a mixture thereof, unless explicitly mentioned for a particular isomer. There is. See, for example, WO01 / 062726.

The compounds of the present invention improves the function of the .alpha.5-containing GABA _A R, i.e., they are .alpha.5-containing GABA _A R agonists (e.g., .alpha.5-containing GABA _A receptor positive allosteric modulators) are, GABA agonistic Cl ^- current Can be increased.

The invention further provides a pharmaceutical composition comprising one or more compounds of the invention with a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition of the present application may further comprise a second therapeutic agent, such as an antipsychotic, memantine or AChE-I.

The present invention further relates to cognitive disorders associated with the CNS disorder that are responsive to the positive allosteric modulator of the α5-containing GABA _A receptor, such as age-related cognitive impairment, mild cognitive impairment (MCI), forgetfulness MCI (aMCI). Age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), precursor AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, muscle atrophic side Methods for treating cord sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorders, fragile X disorders, Let's syndrome, compulsive behavior and substance addiction. offer. In certain embodiments, the methods include age-related cognitive impairment, mild cognitive impairment (MCI), forgetfulness MCI (aMCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), cognition. Disease, Alzheimer's disease (AD), precursor AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, muscular atrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, It is a method of treating Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Let's syndrome, compulsive behavior and substance addiction. In certain embodiments, treatment includes prevention of CNS disorders as described herein (eg, those described herein) or delay in their progression. In certain embodiments, treatment comprises alleviating, ameliorating or delaying the progression of one or more symptoms associated with a CNS disorder. In certain embodiments, the symptom being treated is cognitive impairment or agnosia. In another aspect of the invention, a method of preserving or ameliorating cognitive function in a subject in need of conserving or improving cognitive function is provided, wherein the method provides the subject with a therapeutically effective amount of the invention. Includes the administration of a compound of or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof.

Various CNS disorders with cognitive impairment (eg, age-related cognitive impairment, mild cognitive impairment (MCI), forgetfulness MCI (aMCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), cognition Disease, Alzheimer's disease (AD), precursor AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, muscular atrophic lateral sclerosis (ALS), cognitive impairment associated with cancer treatment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Let's syndrome, compulsive behavior and substance addiction) can have a variety of etiologies. However, the symptoms of cognitive impairment in each of the above disorders can have overlapping causes. Thus, a composition or treatment method for treating cognitive impairment in one CNS disorder can also treat cognitive impairment in another.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式Ｉにおいて：
Ｕと、αおよびβによって表される２個の炭素原子とが一緒になって、０個〜２個の窒素原子を有する５員または６員の芳香環を形成し；
Ａは、Ｃ、ＣＲ^６、またはＮであり；
ＢおよびＦは各々独立して、Ｃ、ＣＲ^６、およびＮから選択され、ここでＢとＦとの両方がＮであることはできず；
Ｄは、Ｎ、ＮＲ^７、Ｏ、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｅは、Ｎ、ＮＲ^７、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｗは、Ｎ、ＮＲ^７、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｘは、Ｎ、ＮＲ^７、Ｏ、ＣＲ^６またはＣ（Ｒ^６）_２であり；
ＹおよびＺは各々独立して、Ｃ、ＣＲ^６、およびＮから選択され、ここでＹとＺとの両方がＮであることはできず；
Ｖは、ＣまたはＣＲ^６であるか、
あるいはＺがＣまたはＣＲ^６である場合、Ｖは、Ｃ、ＣＲ^６、またはＮであり；
ここでＸ、Ｙ、Ｚ、ＶおよびＷによって形成される環が

である場合、Ｒ^２は、−ＯＲ^８、−ＳＲ^８、−（ＣＨ_２）_ｎＯＲ^８、−（ＣＨ_２）_ｎＯ（ＣＨ_２）_ｎＲ^８、−（ＣＨ_２）_ｐＲ^８および−（ＣＨ_２）_ｎＮ（Ｒ’’）Ｒ^１０であり；ここでＲ^２は独立して、０個〜５個のＲ’で置換されており；
ｍおよびｎは独立して、０〜４から選択される整数であり；
ｐは、２〜４から選択される整数であり；
結合

の各存在は、単結合または二重結合のいずれかであり；
Ｒ^１、Ｒ^２、Ｒ^４、およびＲ^５の各存在は、各々独立して：
ハロゲン、−Ｒ、−ＯＲ、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３、−ＳｉＲ_３、−Ｎ（Ｒ）_２、−ＳＲ、−ＳＯＲ、−ＳＯ_２Ｒ、−ＳＯ_２Ｎ（Ｒ）_２、−ＳＯ_３Ｒ、−（ＣＲ_２）_１〜３Ｒ、−（ＣＲ_２）_１〜３−ＯＲ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３Ｒ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３ＯＲ、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＣＨ_２Ｃ（Ｏ）Ｒ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｎ（Ｒ）_２、−Ｃ（Ｓ）Ｎ（Ｒ）_２、−（ＣＲ_２）_０〜３ＮＨＣ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＮ（Ｒ）_２、−Ｎ（Ｒ）ＳＯ_２Ｒ、−Ｎ（Ｒ）ＳＯ_２Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｓ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｓ）Ｎ（Ｒ）_２、−Ｎ（ＣＯＲ）ＣＯＲ、−Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＨ）Ｎ（Ｒ）_２、−Ｃ（Ｏ）Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＯＲ）Ｒ、−ＯＰ（Ｏ）（ＯＲ）_２、−Ｐ（Ｏ）（Ｒ）_２、−Ｐ（Ｏ）（ＯＲ）_２、および−Ｐ（Ｏ）（Ｈ）（ＯＲ）から選択され；
Ｒ^３は、存在しないか、または：
ハロゲン、−Ｒ、−ＯＲ、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３、−ＳｉＲ_３、−Ｎ（Ｒ）_２、−ＳＲ、−ＳＯＲ、−ＳＯ_２Ｒ、−ＳＯ_２Ｎ（Ｒ）_２、−ＳＯ_３Ｒ、−（ＣＲ_２）_１〜３Ｒ、−（ＣＲ_２）_１〜３−ＯＲ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３Ｒ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３ＯＲ、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＣＨ_２Ｃ（Ｏ）Ｒ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｎ（Ｒ）_２、−Ｃ（Ｓ）Ｎ（Ｒ）_２、−（ＣＲ_２）_０〜３ＮＨＣ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＮ（Ｒ）_２、−Ｎ（Ｒ）ＳＯ_２Ｒ、−Ｎ（Ｒ）ＳＯ_２Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｓ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｓ）Ｎ（Ｒ）_２、−Ｎ（ＣＯＲ）ＣＯＲ、−Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＨ）Ｎ（Ｒ）_２、−Ｃ（Ｏ）Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＯＲ）Ｒ、−ＯＰ（Ｏ）（ＯＲ）_２、−Ｐ（Ｏ）（Ｒ）_２、−Ｐ（Ｏ）（ＯＲ）_２、および−Ｐ（Ｏ）（Ｈ）（ＯＲ）から選択され；
各Ｒ^６は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
各Ｒ^７は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
各Ｒ^８は独立して、−（Ｃ１〜Ｃ６）アルキル、−（Ｃ３〜Ｃ１０）−シクロアルキル、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ^８の各存在は独立して、０個〜５個のＲ’で置換されており；
各Ｒ^１０は独立して、−（Ｃ３〜Ｃ１０）−シクロアルキル、３員〜１０員のヘテロシクリル−、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ^１０の各存在は独立して、０個〜５個のＲ’で置換されており；
各Ｒは独立して：
Ｈ−、
（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ３〜Ｃ１０）−シクロアルキル−、
（Ｃ３〜Ｃ１０）−シクロアルケニル−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−、
（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
３員〜１０員のヘテロシクリル−、
（３員〜１０員のヘテロシクリル）−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
５員〜１０員のヘテロアリール−、
（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ１２）−脂肪族−、
（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−；および
（５員〜１０員のヘテロアリール）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）−脂肪族−
から選択され；
ここでこのヘテロシクリルは、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される１個〜４個のヘテロ原子を有し、そしてこのヘテロアリールは、Ｎ、ＮＨ、Ｏ、およびＳから独立して選択される１個〜４個のヘテロ原子を有し；
ここでＲの各存在は独立して、０個〜５個のＲ’で置換されているか；
あるいは２個のＲ基が同じ原子に結合している場合、これらの２個のＲ基は、これらが結合している原子と一緒になって、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される０個〜４個のヘテロ原子を有する３員〜１０員の芳香族または非芳香族の環を形成し得、ここでこの環は、０個〜５個のＲ’で必要に応じて置換されており、そしてこの環は、（Ｃ６〜Ｃ１０）アリール、５員〜１０員のヘテロアリール、（Ｃ３〜Ｃ１０）シクロアルキル、または３員〜１０員のヘテロシクリルに必要に応じて縮合しており；
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ_２ＯＲ’’、−ＣＨ_２ＮＲ’’_２、−Ｃ（Ｏ）Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ’’）_２から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、−（Ｃ１〜Ｃ６）−脂肪族、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択され、ここでＲ’’の各存在は、ハロゲン、−Ｒ^ｏ、−ＯＲ^ｏ、オキソ、−ＣＨ_２ＯＲ^ｏ、−ＣＨ_２ＮＲ^ｏ _２、−Ｃ（Ｏ）Ｎ（Ｒ^ｏ）_２、−Ｃ（Ｏ）ＯＲ^ｏ、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ^ｏ）_２から選択される０個〜３個の置換基で独立して置換されており、ここでＲ^ｏの各存在は独立して、−（Ｃ１〜Ｃ６）−脂肪族、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、および（Ｃ６〜Ｃ１０）−アリール−から選択される。 Benzodiazepine Derivatives The present invention describes the formula I:

A compound of, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, provided in Formula I:
U and the two carbon atoms represented by α and β together form a 5- or 6-membered aromatic ring with 0 to 2 nitrogen atoms;
A is C, CR ⁶ , or N;
B and F are independently ^{selected from C, CR 6} , and N, where both B and F cannot be N;
D is N, NR ⁷ , O, CR ⁶ or C (R ⁶ ) ₂ ;
E is N, NR ⁷ , CR ⁶ or C (R ⁶ ) ₂ ;
W is N, NR ⁷ , CR ⁶ or C (R ⁶ ) ₂ ;
X is N, NR ⁷ , O, CR ⁶ or C (R ⁶ ) ₂ ;
Y and Z are independently ^{selected from C, CR 6} , and N, where both Y and Z cannot be N;
V is C or CR ⁶ or
Alternatively, if Z is C or CR ⁶ , then V is C, CR ⁶ , or N;
Here the ring formed by X, Y, Z, V and W

If, then R ² is −OR ⁸ , −SR ⁸ , − (CH ₂ ) _n OR ⁸ , − (CH ₂ ) _n O (CH ₂ ) _n R ⁸ , − (CH ₂ ) _p R ⁸ and − (CH ₂ ) _n N (R'') R ¹⁰ ; where R ² is independently substituted with 0-5 R';
m and n are integers independently selected from 0 to 4;
p is an integer selected from 2-4;
Join

Each presence of is either a single bond or a double bond;
The ^{existence of R 1} , R ² , R ⁴ , and R ⁵ is independent of each other:
Halogen, -R, -OR, -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ , -SiR ₃ , -N (R) ₂ , -SR, -SOR, -SO ₂ R, -SO ₂ N (R) ₂ , -SO ₃ R,-(CR ₂ ) _1-3 R,-(CR ₂ ) _1-3- OR,-(CR ₂ ) _0-3 -C (O) NR (CR ₂₎ ) _0-3 R,-(CR ₂ ) _0-3 -C (O) NR (CR ₂ ) _0-3 OR, -C (O) R, -C (O) C (O) R, -C ( O) CH ₂ C (O) R, -C (S) R, -C (S) OR, -C (O) OR, -C (O) C (O) OR, -C (O) C (O) ) N (R) ₂ , -OC (O) R, -C (O) N (R) ₂ , -OC (O) N (R) ₂ , -C (S) N (R) ₂ ,-(CR) ₂ ) _{0 to 3} NHC (O) R, -N (R) N (R) COR, -N (R) N (R) C (O) OR, -N (R) N (R) CON (R) ₂ , -N (R) SO ₂ R, -N (R) SO ₂ N (R) ₂ , -N (R) C (O) OR, -N (R) C (O) R, -N (R) ) C (S) R, -N (R) C (O) N (R) ₂ , -N (R) C (S) N (R) ₂ , -N (COR) COR, -N (OR) R , -C (= NH) N (R) ₂ , -C (O) N (OR) R, -C (= NOR) R, -OP (O) (OR) ₂ , -P (O) (R) ₂ , -P (O) (OR) ₂ , and -P (O) (H) (OR);
R ³ does not exist or:
Halogen, -R, -OR, -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ , -SiR ₃ , -N (R) ₂ , -SR, -SOR, -SO ₂ R, -SO ₂ N (R) ₂ , -SO ₃ R,-(CR ₂ ) _1-3 R,-(CR ₂ ) _1-3- OR,-(CR ₂ ) _0-3 -C (O) NR (CR ₂₎ ) _0-3 R,-(CR ₂ ) _0-3 -C (O) NR (CR ₂ ) _0-3 OR, -C (O) R, -C (O) C (O) R, -C ( O) CH ₂ C (O) R, -C (S) R, -C (S) OR, -C (O) OR, -C (O) C (O) OR, -C (O) C (O) ) N (R) ₂ , -OC (O) R, -C (O) N (R) ₂ , -OC (O) N (R) ₂ , -C (S) N (R) ₂ ,-(CR) ₂ ) _{0 to 3} NHC (O) R, -N (R) N (R) COR, -N (R) N (R) C (O) OR, -N (R) N (R) CON (R) ₂ , -N (R) SO ₂ R, -N (R) SO ₂ N (R) ₂ , -N (R) C (O) OR, -N (R) C (O) R, -N (R) ) C (S) R, -N (R) C (O) N (R) ₂ , -N (R) C (S) N (R) ₂ , -N (COR) COR, -N (OR) R , -C (= NH) N (R) ₂ , -C (O) N (OR) R, -C (= NOR) R, -OP (O) (OR) ₂ , -P (O) (R) ₂ , -P (O) (OR) ₂ , and -P (O) (H) (OR);
Each ^{R 6} is independently, -H or - be (C1 -C6) alkyl;
Each R ⁷ is independently -H or- (C1-C6) alkyl;
Each R ⁸ is independently a-(C1-C6) alkyl,-(C3-C10) -cycloalkyl, (C6-C10) -aryl, or 5- to 10-membered heteroaryl, where R ^{8 is.} Each existence of is independently replaced by 0-5 R';
Each R ¹⁰ is independently a-(C3-C10) -cycloalkyl, 3-member to 10-membered heterocyclyl-, (C6-C10) -aryl, or 5- to 10-membered heteroaryl, where R ^{Each of the 10} beings is independently replaced by 0-5 R';
Each R is independent:
H-,
(C1-C12) -aliphatic-,
(C3 to C10) -Cycloalkyl-,
(C3 to C10) -Cycloalkenyl-,
[(C3 to C10) -cycloalkyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkyl] -O- (C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl] -O- (C1 to C12) -aliphatic-,
(C6 to C10) -aryl-,
(C6 to C10) -aryl- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-O- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-N (R'')-(C1 to C12) aliphatic-,
Heterocyclyl of 3 to 10 members-,
(3-10 member heterocyclyl)-(C1-C12) Aliphatic-,
(3-10 member heterocyclyl) -O- (C1-C12) aliphatic-,
(3-10 member heterocyclyl) -N (R'')-(C1-C12) aliphatic-,
5-10 member heteroaryl-,
(5- to 10-membered heteroaryl)-(C1-C12) -aliphatic-,
(5-membered to 10-membered heteroaryl) -O- (C1-C12) -aliphatic-; and (5-membered to 10-membered heteroaryl) -N (R'')-(C1-C12) -aliphatic −
Selected from;
Here the heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO ₂ , and the heteroaryl is N, NH, O, And has 1 to 4 heteroatoms selected independently of S;
Where each existence of R is independently replaced by 0-5 R';
Alternatively, if two R groups are attached to the same atom, these two R groups, together with the atom to which they are attached, are N, NH, O, S, SO, and SO. It is possible to form a 3- to 10-membered aromatic or non-aromatic ring with 0 to 4 heteroatoms independently selected from _{2, where the ring is 0 to 5 Rs.} 'Is substituted as needed, and this ring is required for (C6-C10) aryl, 5-membered to 10-membered heteroaryl, (C3-C10) cycloalkyl, or 3-membered to 10-membered heterocyclyl. Condensed according to;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, -CH ₂ OR " _{, -CH 2} NR" ₂ , and -C (O) N (R'. ') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R') ₂ ;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl,-(C1-C6) -aryl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl. 5, 10-membered heteroaryl-, (C6-C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1) ~ C6) -alkyl-, (5-member to 10-membered heteroaryl) -O- (C1-C6) -alkyl-, and (C6-C10) -aryl-O- (C1-C6) -alkyl- Here, each presence of R'' is halogen, -R ^o , -OR ^o , oxo, -CH ₂ OR ^o , -CH ₂ NR ^o ₂ , -C (O) N (R ^o ) ₂ ,-. Independently substituted with 0 to 3 substituents selected from C (O) OR ^o , -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R ^o ) _2. and, wherein each occurrence of ^{R o} is independently, - (C1 -C6) - aliphatic, (C3 -C6) - cycloalkyl, 3-6 membered heterocyclyl, 5- to 10-membered heteroaryl -, And (C6 to C10) -aryl- are selected.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式Ｉにおいて：
Ｕと、αおよびβによって表される２個の炭素原子とが一緒になって、０個〜２個の窒素原子を有する５員または６員の芳香環を形成し；
Ａは、Ｃ、ＣＲ^６、またはＮであり；
ＢおよびＦは各々独立して、Ｃ、ＣＲ^６、およびＮから選択され、ここでＢとＦとの両方がＮであることはできず；
Ｄは、Ｎ、ＮＲ^７、Ｏ、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｅは、Ｎ、ＮＲ^７、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｗは、Ｎ、ＮＲ^７、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｘは、Ｎ、ＮＲ^７、Ｏ、ＣＲ^６またはＣ（Ｒ^６）_２であり；
ＹおよびＺは各々独立して、Ｃ、ＣＲ^６、およびＮから選択され、ここでＹとＺとの両方がＮであることはできず；
Ｖは、ＣまたはＣＲ^６であるか、
あるいはＺがＣまたはＣＲ^６である場合、Ｖは、Ｃ、ＣＲ^６、またはＮであり；
ここでＸ、Ｙ、Ｚ、ＶおよびＷによって形成される環が

である場合、Ｒ^２は、−ＯＲ^８、−ＳＲ^８、−（ＣＨ_２）_ｎＯＲ^８、−（ＣＨ_２）_ｎＯ（ＣＨ_２）_ｎＲ^８、−（ＣＨ_２）_ｐＲ^８および−（ＣＨ_２）_ｎＮ（Ｒ’’）Ｒ^１０であり；ここでＲ^２は独立して、０個〜５個のＲ’で置換されており；
ｍおよびｎは独立して、０〜４から選択される整数であり；
ｐは、２〜４から選択される整数であり；
結合

の各存在は、単結合または二重結合のいずれかであり；
Ｒ^１、Ｒ^２、Ｒ^４、およびＲ^５の各存在は、各々独立して：
ハロゲン、−Ｒ、−ＯＲ、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３、−ＳｉＲ_３、−Ｎ（Ｒ）_２、−ＳＲ、−ＳＯＲ、−ＳＯ_２Ｒ、−ＳＯ_２Ｎ（Ｒ）_２、−ＳＯ_３Ｒ、−（ＣＲ_２）_１〜３Ｒ、−（ＣＲ_２）_１〜３−ＯＲ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３Ｒ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３ＯＲ、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＣＨ_２Ｃ（Ｏ）Ｒ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｎ（Ｒ）_２、−Ｃ（Ｓ）Ｎ（Ｒ）_２、−（ＣＲ_２）_０〜３ＮＨＣ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＮ（Ｒ）_２、−Ｎ（Ｒ）ＳＯ_２Ｒ、−Ｎ（Ｒ）ＳＯ_２Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｓ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｓ）Ｎ（Ｒ）_２、−Ｎ（ＣＯＲ）ＣＯＲ、−Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＨ）Ｎ（Ｒ）_２、−Ｃ（Ｏ）Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＯＲ）Ｒ、−ＯＰ（Ｏ）（ＯＲ）_２、−Ｐ（Ｏ）（Ｒ）_２、−Ｐ（Ｏ）（ＯＲ）_２、および−Ｐ（Ｏ）（Ｈ）（ＯＲ）から選択され；
Ｒ^３は、存在しないか、または：
ハロゲン、−Ｒ、−ＯＲ、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３、−ＳｉＲ_３、−Ｎ（Ｒ）_２、−ＳＲ、−ＳＯＲ、−ＳＯ_２Ｒ、−ＳＯ_２Ｎ（Ｒ）_２、−ＳＯ_３Ｒ、−（ＣＲ_２）_１〜３Ｒ、−（ＣＲ_２）_１〜３−ＯＲ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３Ｒ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３ＯＲ、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＣＨ_２Ｃ（Ｏ）Ｒ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｎ（Ｒ）_２、−Ｃ（Ｓ）Ｎ（Ｒ）_２、−（ＣＲ_２）_０〜３ＮＨＣ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＮ（Ｒ）_２、−Ｎ（Ｒ）ＳＯ_２Ｒ、−Ｎ（Ｒ）ＳＯ_２Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｓ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｓ）Ｎ（Ｒ）_２、−Ｎ（ＣＯＲ）ＣＯＲ、−Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＨ）Ｎ（Ｒ）_２、−Ｃ（Ｏ）Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＯＲ）Ｒ、−ＯＰ（Ｏ）（ＯＲ）_２、−Ｐ（Ｏ）（Ｒ）_２、−Ｐ（Ｏ）（ＯＲ）_２、および−Ｐ（Ｏ）（Ｈ）（ＯＲ）から選択され；
各Ｒ^６は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
各Ｒ^７は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
各Ｒ^８は独立して、−（Ｃ１〜Ｃ６）アルキル、−（Ｃ３〜Ｃ１０）−シクロアルキル、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ^８の各存在は独立して、０個〜５個のＲ’で置換されており；
各Ｒ^１０は独立して、−（Ｃ３〜Ｃ１０）−シクロアルキル、３員〜１０員のヘテロシクリル−、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ^１０の各存在は独立して、０個〜５個のＲ’で置換されており；
各Ｒは独立して：
Ｈ−、
（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ３〜Ｃ１０）−シクロアルキル−、
（Ｃ３〜Ｃ１０）−シクロアルケニル−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−、
（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
３員〜１０員のヘテロシクリル−、
（３員〜１０員のヘテロシクリル）−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
５員〜１０員のヘテロアリール−、
（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ１２）−脂肪族−、
（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−；および
（５員〜１０員のヘテロアリール）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）−脂肪族−
から選択され；
ここでこのヘテロシクリルは、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される１個〜４個のヘテロ原子を有し、そしてこのヘテロアリールは、Ｎ、ＮＨ、Ｏ、およびＳから独立して選択される１個〜４個のヘテロ原子を有し；
ここでＲの各存在は独立して、０個〜５個のＲ’で置換されているか；
あるいは２個のＲ基が同じ原子に結合している場合、これらの２個のＲ基は、これらが結合している原子と一緒になって、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される０個〜４個のヘテロ原子を有する３員〜１０員の芳香族または非芳香族の環を形成し得、ここでこの環は、０個〜５個のＲ’で必要に応じて置換されており、そしてこの環は、（Ｃ６〜Ｃ１０）アリール、５員〜１０員のヘテロアリール、（Ｃ３〜Ｃ１０）シクロアルキル、または３員〜１０員のヘテロシクリルに必要に応じて縮合しており；
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ_２ＯＲ’’、−ＣＨ_２ＮＲ’’_２、−Ｃ（Ｏ）Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ’’）_２から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択される。 In some embodiments, the present invention relates to Formula I :.

A compound of, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, provided in Formula I:
U and the two carbon atoms represented by α and β together form a 5- or 6-membered aromatic ring with 0 to 2 nitrogen atoms;
A is C, CR ⁶ , or N;
B and F are independently ^{selected from C, CR 6} , and N, where both B and F cannot be N;
D is N, NR ⁷ , O, CR ⁶ or C (R ⁶ ) ₂ ;
E is N, NR ⁷ , CR ⁶ or C (R ⁶ ) ₂ ;
W is N, NR ⁷ , CR ⁶ or C (R ⁶ ) ₂ ;
X is N, NR ⁷ , O, CR ⁶ or C (R ⁶ ) ₂ ;
Y and Z are independently ^{selected from C, CR 6} , and N, where both Y and Z cannot be N;
V is C or CR ⁶ or
Alternatively, if Z is C or CR ⁶ , then V is C, CR ⁶ , or N;
Here the ring formed by X, Y, Z, V and W

If, then R ² is −OR ⁸ , −SR ⁸ , − (CH ₂ ) _n OR ⁸ , − (CH ₂ ) _n O (CH ₂ ) _n R ⁸ , − (CH ₂ ) _p R ⁸ and − (CH ₂ ) _n N (R'') R ¹⁰ ; where R ² is independently substituted with 0-5 R';
m and n are integers independently selected from 0 to 4;
p is an integer selected from 2-4;
Join

Each presence of is either a single bond or a double bond;
The ^{existence of R 1} , R ² , R ⁴ , and R ⁵ is independent of each other:
Halogen, -R, -OR, -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ , -SiR ₃ , -N (R) ₂ , -SR, -SOR, -SO ₂ R, -SO ₂ N (R) ₂ , -SO ₃ R,-(CR ₂ ) _1-3 R,-(CR ₂ ) _1-3- OR,-(CR ₂ ) _0-3 -C (O) NR (CR ₂₎ ) _0-3 R,-(CR ₂ ) _0-3 -C (O) NR (CR ₂ ) _0-3 OR, -C (O) R, -C (O) C (O) R, -C ( O) CH ₂ C (O) R, -C (S) R, -C (S) OR, -C (O) OR, -C (O) C (O) OR, -C (O) C (O) ) N (R) ₂ , -OC (O) R, -C (O) N (R) ₂ , -OC (O) N (R) ₂ , -C (S) N (R) ₂ ,-(CR) ₂ ) _{0 to 3} NHC (O) R, -N (R) N (R) COR, -N (R) N (R) C (O) OR, -N (R) N (R) CON (R) ₂ , -N (R) SO ₂ R, -N (R) SO ₂ N (R) ₂ , -N (R) C (O) OR, -N (R) C (O) R, -N (R) ) C (S) R, -N (R) C (O) N (R) ₂ , -N (R) C (S) N (R) ₂ , -N (COR) COR, -N (OR) R , -C (= NH) N (R) ₂ , -C (O) N (OR) R, -C (= NOR) R, -OP (O) (OR) ₂ , -P (O) (R) ₂ , -P (O) (OR) ₂ , and -P (O) (H) (OR);
R ³ does not exist or:
Halogen, -R, -OR, -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ , -SiR ₃ , -N (R) ₂ , -SR, -SOR, -SO ₂ R, -SO ₂ N (R) ₂ , -SO ₃ R,-(CR ₂ ) _1-3 R,-(CR ₂ ) _1-3- OR,-(CR ₂ ) _0-3 -C (O) NR (CR ₂₎ ) _0-3 R,-(CR ₂ ) _0-3 -C (O) NR (CR ₂ ) _0-3 OR, -C (O) R, -C (O) C (O) R, -C ( O) CH ₂ C (O) R, -C (S) R, -C (S) OR, -C (O) OR, -C (O) C (O) OR, -C (O) C (O) ) N (R) ₂ , -OC (O) R, -C (O) N (R) ₂ , -OC (O) N (R) ₂ , -C (S) N (R) ₂ ,-(CR) ₂ ) _{0 to 3} NHC (O) R, -N (R) N (R) COR, -N (R) N (R) C (O) OR, -N (R) N (R) CON (R) ₂ , -N (R) SO ₂ R, -N (R) SO ₂ N (R) ₂ , -N (R) C (O) OR, -N (R) C (O) R, -N (R) ) C (S) R, -N (R) C (O) N (R) ₂ , -N (R) C (S) N (R) ₂ , -N (COR) COR, -N (OR) R , -C (= NH) N (R) ₂ , -C (O) N (OR) R, -C (= NOR) R, -OP (O) (OR) ₂ , -P (O) (R) ₂ , -P (O) (OR) ₂ , and -P (O) (H) (OR);
Each ^{R 6} is independently, -H or - be (C1 -C6) alkyl;
Each R ⁷ is independently -H or- (C1-C6) alkyl;
Each R ⁸ is independently a-(C1-C6) alkyl,-(C3-C10) -cycloalkyl, (C6-C10) -aryl, or 5- to 10-membered heteroaryl, where R ^{8 is.} Each existence of is independently replaced by 0-5 R';
Each R ¹⁰ is independently a-(C3-C10) -cycloalkyl, 3-member to 10-membered heterocyclyl-, (C6-C10) -aryl, or 5- to 10-membered heteroaryl, where R ^{Each of the 10} beings is independently replaced by 0-5 R';
Each R is independent:
H-,
(C1-C12) -aliphatic-,
(C3 to C10) -Cycloalkyl-,
(C3 to C10) -Cycloalkenyl-,
[(C3 to C10) -cycloalkyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkyl] -O- (C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl] -O- (C1 to C12) -aliphatic-,
(C6 to C10) -aryl-,
(C6 to C10) -aryl- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-O- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-N (R'')-(C1 to C12) aliphatic-,
Heterocyclyl of 3 to 10 members-,
(3-10 member heterocyclyl)-(C1-C12) Aliphatic-,
(3-10 member heterocyclyl) -O- (C1-C12) aliphatic-,
(3-10 member heterocyclyl) -N (R'')-(C1-C12) aliphatic-,
5-10 member heteroaryl-,
(5- to 10-membered heteroaryl)-(C1-C12) -aliphatic-,
(5-membered to 10-membered heteroaryl) -O- (C1-C12) -aliphatic-; and (5-membered to 10-membered heteroaryl) -N (R'')-(C1-C12) -aliphatic −
Selected from;
Here the heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO ₂ , and the heteroaryl is N, NH, O, And has 1 to 4 heteroatoms selected independently of S;
Where each existence of R is independently replaced by 0-5 R';
Alternatively, if two R groups are attached to the same atom, these two R groups, together with the atom to which they are attached, are N, NH, O, S, SO, and SO. It is possible to form a 3- to 10-membered aromatic or non-aromatic ring with 0 to 4 heteroatoms independently selected from _{2, where the ring is 0 to 5 Rs.} 'Is substituted as needed, and this ring is required for (C6-C10) aryl, 5-membered to 10-membered heteroaryl, (C3-C10) cycloalkyl, or 3-membered to 10-membered heterocyclyl. Condensed according to;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, -CH ₂ OR " _{, -CH 2} NR" ₂ , and -C (O) N (R'. ') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R') ₂ ;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-. , (C6 to C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1-C6) -alkyl-, (5-membered) It is selected from 10-membered heteroaryl) -O- (C1-C6) -alkyl- and (C6-C10) -aryl-O- (C1-C6) -alkyl-.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式Ｉにおいて：
Ｕと、αおよびβによって表される２個の炭素原子とが一緒になって、０個〜２個の窒素原子を有する５員または６員の芳香環を形成し；
Ａは、Ｃ、ＣＲ^６、またはＮであり；
ＢおよびＦは各々独立して、Ｃ、ＣＲ^６、およびＮから選択され、ここでＢとＦとの両方がＮであることはできず；
Ｄは、Ｎ、ＮＲ^７、Ｏ、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｅは、Ｎ、ＮＲ^７、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｗは、Ｎ、ＮＲ^７、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｘは、Ｎ、ＮＲ^７、Ｏ、ＣＲ^６またはＣ（Ｒ^６）_２であり；
ＹおよびＺは各々独立して、Ｃ、ＣＲ^６、およびＮから選択され、ここでＹとＺとの両方がＮであることはできず；
Ｖは、ＣまたはＣＲ^６であるか、
あるいはＺがＣまたはＣＲ^６である場合、Ｖは、Ｃ、ＣＲ^６、またはＮであり；
ここでＸ、Ｙ、Ｚ、ＶおよびＷによって形成される環が

である場合、Ｒ^２は、−ＯＲ^８、−ＳＲ^８、または−（ＣＨ_２）_ｎＯＲ^８であり；
ｍおよびｎは各々独立して、０〜４から選択される整数であり；
結合

の各存在は、単結合または二重結合のいずれかであり；
Ｒ^１、Ｒ^２、Ｒ^４、およびＲ^５の各存在は、各々独立して：
ハロゲン、−Ｒ、−ＯＲ、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３、−ＳｉＲ_３、−Ｎ（Ｒ）_２、−ＳＲ、−ＳＯＲ、−ＳＯ_２Ｒ、−ＳＯ_２Ｎ（Ｒ）_２、−ＳＯ_３Ｒ、−（ＣＲ_２）_１〜３Ｒ、−（ＣＲ_２）_１〜３−ＯＲ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３Ｒ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３ＯＲ、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＣＨ_２Ｃ（Ｏ）Ｒ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｎ（Ｒ）_２、−Ｃ（Ｓ）Ｎ（Ｒ）_２、−（ＣＲ_２）_０〜３ＮＨＣ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＮ（Ｒ）_２、−Ｎ（Ｒ）ＳＯ_２Ｒ、−Ｎ（Ｒ）ＳＯ_２Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｓ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｓ）Ｎ（Ｒ）_２、−Ｎ（ＣＯＲ）ＣＯＲ、−Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＨ）Ｎ（Ｒ）_２、−Ｃ（Ｏ）Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＯＲ）Ｒ、−ＯＰ（Ｏ）（ＯＲ）_２、−Ｐ（Ｏ）（Ｒ）_２、−Ｐ（Ｏ）（ＯＲ）_２、および−Ｐ（Ｏ）（Ｈ）（ＯＲ）から選択され；
Ｒ^３は、存在しないか、または：
ハロゲン、−Ｒ、−ＯＲ、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３、−ＳｉＲ_３、−Ｎ（Ｒ）_２、−ＳＲ、−ＳＯＲ、−ＳＯ_２Ｒ、−ＳＯ_２Ｎ（Ｒ）_２、−ＳＯ_３Ｒ、−（ＣＲ_２）_１〜３Ｒ、−（ＣＲ_２）_１〜３−ＯＲ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３Ｒ、−（ＣＲ_２）_０〜３−Ｃ（Ｏ）ＮＲ（ＣＲ_２）_０〜３ＯＲ、−Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｒ、−Ｃ（Ｏ）ＣＨ_２Ｃ（Ｏ）Ｒ、−Ｃ（Ｓ）Ｒ、−Ｃ（Ｓ）ＯＲ、−Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）ＯＲ、−Ｃ（Ｏ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｒ、−Ｃ（Ｏ）Ｎ（Ｒ）_２、−ＯＣ（Ｏ）Ｎ（Ｒ）_２、−Ｃ（Ｓ）Ｎ（Ｒ）_２、−（ＣＲ_２）_０〜３ＮＨＣ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｎ（Ｒ）ＣＯＮ（Ｒ）_２、−Ｎ（Ｒ）ＳＯ_２Ｒ、−Ｎ（Ｒ）ＳＯ_２Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｏ）ＯＲ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｓ）Ｒ、−Ｎ（Ｒ）Ｃ（Ｏ）Ｎ（Ｒ）_２、−Ｎ（Ｒ）Ｃ（Ｓ）Ｎ（Ｒ）_２、−Ｎ（ＣＯＲ）ＣＯＲ、−Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＨ）Ｎ（Ｒ）_２、−Ｃ（Ｏ）Ｎ（ＯＲ）Ｒ、−Ｃ（＝ＮＯＲ）Ｒ、−ＯＰ（Ｏ）（ＯＲ）_２、−Ｐ（Ｏ）（Ｒ）_２、−Ｐ（Ｏ）（ＯＲ）_２、および−Ｐ（Ｏ）（Ｈ）（ＯＲ）から選択され；
各Ｒ^６は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
各Ｒ^７は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
各Ｒ^８は独立して、−（Ｃ１〜Ｃ６）アルキル、−（Ｃ３〜Ｃ１０）−シクロアルキル、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ^８の各存在は独立して、０個〜５個のＲ’で置換されており；
各Ｒは独立して：
Ｈ−、
（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ３〜Ｃ１０）−シクロアルキル−、
（Ｃ３〜Ｃ１０）−シクロアルケニル−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−、
（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
３員〜１０員のヘテロシクリル−、
（３員〜１０員のヘテロシクリル）−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
５員〜１０員のヘテロアリール−、
（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ１２）−脂肪族−、および
（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−
から選択され；
ここでこのヘテロシクリルは、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される１個〜４個のヘテロ原子を有し、そしてこのヘテロアリールは、Ｎ、ＮＨ、Ｏ、およびＳから独立して選択される１個〜４個のヘテロ原子を有し；
ここでＲの各存在は独立して、０個〜５個のＲ’で置換されているか；
あるいは２個のＲ基が同じ原子に結合している場合、これらの２個のＲ基は、これらが結合している原子と一緒になって、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される０個〜４個のヘテロ原子を有する３員〜１０員の芳香族または非芳香族の環を形成し得、ここでこの環は、０個〜５個のＲ’で必要に応じて置換されており、そしてこの環は、（Ｃ６〜Ｃ１０）アリール、５員〜１０員のヘテロアリール、（Ｃ３〜Ｃ１０）シクロアルキル、または３員〜１０員のヘテロシクリルに必要に応じて縮合しており；
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ_２ＯＲ’’、−ＣＨ_２ＮＲ’’_２、−Ｃ（Ｏ）Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ’’）_２から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択される。 Some embodiments include Formula I :.

A compound of, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, provided in Formula I:
U and the two carbon atoms represented by α and β together form a 5- or 6-membered aromatic ring with 0 to 2 nitrogen atoms;
A is C, CR ⁶ , or N;
B and F are independently ^{selected from C, CR 6} , and N, where both B and F cannot be N;
D is N, NR ⁷ , O, CR ⁶ or C (R ⁶ ) ₂ ;
E is N, NR ⁷ , CR ⁶ or C (R ⁶ ) ₂ ;
W is N, NR ⁷ , CR ⁶ or C (R ⁶ ) ₂ ;
X is N, NR ⁷ , O, CR ⁶ or C (R ⁶ ) ₂ ;
Y and Z are independently ^{selected from C, CR 6} , and N, where both Y and Z cannot be N;
V is C or CR ⁶ or
Alternatively, if Z is C or CR ⁶ , then V is C, CR ⁶ , or N;
Here the ring formed by X, Y, Z, V and W

If, then R ² is −OR ⁸ , −SR ⁸ , or − (CH ₂ ) _n OR ⁸ ;
m and n are integers independently selected from 0 to 4;
Join

Each presence of is either a single bond or a double bond;
The ^{existence of R 1} , R ² , R ⁴ , and R ⁵ is independent of each other:
Halogen, -R, -OR, -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ , -SiR ₃ , -N (R) ₂ , -SR, -SOR, -SO ₂ R, -SO ₂ N (R) ₂ , -SO ₃ R,-(CR ₂ ) _1-3 R,-(CR ₂ ) _1-3- OR,-(CR ₂ ) _0-3 -C (O) NR (CR ₂₎ ) _0-3 R,-(CR ₂ ) _0-3 -C (O) NR (CR ₂ ) _0-3 OR, -C (O) R, -C (O) C (O) R, -C ( O) CH ₂ C (O) R, -C (S) R, -C (S) OR, -C (O) OR, -C (O) C (O) OR, -C (O) C (O) ) N (R) ₂ , -OC (O) R, -C (O) N (R) ₂ , -OC (O) N (R) ₂ , -C (S) N (R) ₂ ,-(CR) ₂ ) _{0 to 3} NHC (O) R, -N (R) N (R) COR, -N (R) N (R) C (O) OR, -N (R) N (R) CON (R) ₂ , -N (R) SO ₂ R, -N (R) SO ₂ N (R) ₂ , -N (R) C (O) OR, -N (R) C (O) R, -N (R) ) C (S) R, -N (R) C (O) N (R) ₂ , -N (R) C (S) N (R) ₂ , -N (COR) COR, -N (OR) R , -C (= NH) N (R) ₂ , -C (O) N (OR) R, -C (= NOR) R, -OP (O) (OR) ₂ , -P (O) (R) ₂ , -P (O) (OR) ₂ , and -P (O) (H) (OR);
R ³ does not exist or:
Halogen, -R, -OR, -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ , -SiR ₃ , -N (R) ₂ , -SR, -SOR, -SO ₂ R, -SO ₂ N (R) ₂ , -SO ₃ R,-(CR ₂ ) _1-3 R,-(CR ₂ ) _1-3- OR,-(CR ₂ ) _0-3 -C (O) NR (CR ₂₎ ) _0-3 R,-(CR ₂ ) _0-3 -C (O) NR (CR ₂ ) _0-3 OR, -C (O) R, -C (O) C (O) R, -C ( O) CH ₂ C (O) R, -C (S) R, -C (S) OR, -C (O) OR, -C (O) C (O) OR, -C (O) C (O) ) N (R) ₂ , -OC (O) R, -C (O) N (R) ₂ , -OC (O) N (R) ₂ , -C (S) N (R) ₂ ,-(CR) ₂ ) _{0 to 3} NHC (O) R, -N (R) N (R) COR, -N (R) N (R) C (O) OR, -N (R) N (R) CON (R) ₂ , -N (R) SO ₂ R, -N (R) SO ₂ N (R) ₂ , -N (R) C (O) OR, -N (R) C (O) R, -N (R) ) C (S) R, -N (R) C (O) N (R) ₂ , -N (R) C (S) N (R) ₂ , -N (COR) COR, -N (OR) R , -C (= NH) N (R) ₂ , -C (O) N (OR) R, -C (= NOR) R, -OP (O) (OR) ₂ , -P (O) (R) ₂ , -P (O) (OR) ₂ , and -P (O) (H) (OR);
Each ^{R 6} is independently, -H or - be (C1 -C6) alkyl;
Each R ⁷ is independently -H or- (C1-C6) alkyl;
Each R ⁸ is independently a-(C1-C6) alkyl,-(C3-C10) -cycloalkyl, (C6-C10) -aryl, or 5- to 10-membered heteroaryl, where R ^{8 is.} Each existence of is independently replaced by 0-5 R';
Each R is independent:
H-,
(C1-C12) -aliphatic-,
(C3 to C10) -Cycloalkyl-,
(C3 to C10) -Cycloalkenyl-,
[(C3 to C10) -cycloalkyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkyl] -O- (C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl] -O- (C1 to C12) -aliphatic-,
(C6 to C10) -aryl-,
(C6 to C10) -aryl- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-O- (C1 to C12) aliphatic-,
Heterocyclyl of 3 to 10 members-,
(3-10 member heterocyclyl)-(C1-C12) Aliphatic-,
(3-10 member heterocyclyl) -O- (C1-C12) aliphatic-,
5-10 member heteroaryl-,
(5-member to 10-membered heteroaryl)-(C1-C12) -aliphatic-and (5-member to 10-membered heteroaryl) -O- (C1-C12) -aliphatic-
Selected from;
Here the heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO ₂ , and the heteroaryl is N, NH, O, And has 1 to 4 heteroatoms selected independently of S;
Where each existence of R is independently replaced by 0-5 R';
Alternatively, if two R groups are attached to the same atom, these two R groups, together with the atom to which they are attached, are N, NH, O, S, SO, and SO. It is possible to form a 3- to 10-membered aromatic or non-aromatic ring with 0 to 4 heteroatoms independently selected from _{2, where the ring is 0 to 5 Rs.} 'Is substituted as needed, and this ring is required for (C6-C10) aryl, 5-membered to 10-membered heteroaryl, (C3-C10) cycloalkyl, or 3-membered to 10-membered heterocyclyl. Condensed according to;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, -CH ₂ OR " _{, -CH 2} NR" ₂ , and -C (O) N (R'. ') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R') ₂ ;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-. , (C6 to C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1-C6) -alkyl-, (5-membered) It is selected from 10-membered heteroaryl) -O- (C1-C6) -alkyl- and (C6-C10) -aryl-O- (C1-C6) -alkyl-.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式Ｉにおいて：
Ｕと、αおよびβによって表される２個の炭素原子とが一緒になって、０個〜２個の窒素原子を有する５員または６員の芳香環を形成し；
Ａは、Ｃ、ＣＲ^６、またはＮであり；
ＢおよびＦは各々独立して、Ｃ、ＣＲ^６、およびＮから選択され、ここでＢとＦとの両方がＮであることはできず；
Ｄは、Ｎ、ＮＲ^７、Ｏ、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｅは、Ｎ、ＮＲ^７、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｗは、Ｎ、ＮＲ^７、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｘは、Ｎ、ＮＲ^７、Ｏ、ＣＲ^６またはＣ（Ｒ^６）_２であり；
ＹおよびＺは各々独立して、Ｃ、ＣＲ^６、およびＮから選択され、ここでＹとＺとの両方がＮであることはできず；
Ｖは、ＣまたはＣＲ^６であるか、
あるいはＺがＣまたはＣＲ^６である場合、Ｖは、Ｃ、ＣＲ^６、またはＮであり；
ここでＸ、Ｙ、Ｚ、ＶおよびＷによって形成される環が

である場合、Ｒ^２は、−（ＣＨ_２）_ｎＯＲ^８または−（ＣＨ_２）_ｎＯ（ＣＨ_２）_ｎＲ^８であり；ここでＲ^２は独立して、０個〜５個のＲ’で置換されており；
ｍおよびｎは独立して、０〜４から選択される整数であり；
ｐは、２〜４から選択される整数であり；
結合

の各存在は、単結合または二重結合のいずれかであり；
各Ｒ^１は独立して、ハロゲン、−Ｒ、および−ＯＲから選択され；
Ｒ^２は：ハロゲン、−Ｒおよび−（ＣＲ_２）_１〜３−ＯＲから選択され；
Ｒ^３は：−Ｒおよび−ＣＮから選択され；
Ｒ^４およびＲ^５は各々独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
各Ｒ^６は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
各Ｒ^７は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
各Ｒ^８は独立して、−（Ｃ１〜Ｃ６）アルキル、−（Ｃ３〜Ｃ１０）−シクロアルキル、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ^８の各存在は独立して、０個〜５個のＲ’で置換されており；
各Ｒは独立して：
Ｈ−、
（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ３〜Ｃ１０）−シクロアルキル−、
（Ｃ３〜Ｃ１０）−シクロアルケニル−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−、
（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
３員〜１０員のヘテロシクリル−、
（３員〜１０員のヘテロシクリル）−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
５員〜１０員のヘテロアリール−、
（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ１２）−脂肪族−、
（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−；および
（５員〜１０員のヘテロアリール）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）−脂肪族−
から選択され；
ここでこのヘテロシクリルは、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される１個〜４個のヘテロ原子を有し、そしてこのヘテロアリールは、Ｎ、ＮＨ、Ｏ、およびＳから独立して選択される１個〜４個のヘテロ原子を有し；
ここでＲの各存在は独立して、０個〜５個のＲ’で置換されているか；
あるいは２個のＲ基が同じ原子に結合している場合、これらの２個のＲ基は、これらが結合している原子と一緒になって、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される０個〜４個のヘテロ原子を有する３員〜１０員の芳香族または非芳香族の環を形成し得、ここでこの環は、０個〜５個のＲ’で必要に応じて置換されており、そしてこの環は、（Ｃ６〜Ｃ１０）アリール、５員〜１０員のヘテロアリール、（Ｃ３〜Ｃ１０）シクロアルキル、または３員〜１０員のヘテロシクリルに必要に応じて縮合しており；
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ_２ＯＲ’’、−ＣＨ_２ＮＲ’’_２、−Ｃ（Ｏ）Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ’’）_２から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、−（Ｃ１〜Ｃ６）−脂肪族、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択され、ここでＲ’’の各存在は：ハロゲン、−Ｒ^ｏ、−ＯＲ^ｏ、オキソ、−ＣＨ_２ＯＲ^ｏ、−ＣＨ_２Ｎ（Ｒ^ｏ）_２、−Ｃ（Ｏ）Ｎ（Ｒ^ｏ）_２、−Ｃ（Ｏ）ＯＲ^ｏ、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ^ｏ）_２から選択される０個〜５個の置換基で独立して置換されており、ここでＲ^ｏの各存在は独立して、−（Ｃ１〜Ｃ６）−脂肪族、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、および（Ｃ６〜Ｃ１０）−アリール−から選択される。 The present invention describes the formula I:

A compound of, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, provided in Formula I:
U and the two carbon atoms represented by α and β together form a 5- or 6-membered aromatic ring with 0 to 2 nitrogen atoms;
A is C, CR ⁶ , or N;
B and F are independently ^{selected from C, CR 6} , and N, where both B and F cannot be N;
D is N, NR ⁷ , O, CR ⁶ or C (R ⁶ ) ₂ ;
E is N, NR ⁷ , CR ⁶ or C (R ⁶ ) ₂ ;
W is N, NR ⁷ , CR ⁶ or C (R ⁶ ) ₂ ;
X is N, NR ⁷ , O, CR ⁶ or C (R ⁶ ) ₂ ;
Y and Z are independently ^{selected from C, CR 6} , and N, where both Y and Z cannot be N;
V is C or CR ⁶ or
Alternatively, if Z is C or CR ⁶ , then V is C, CR ⁶ , or N;
Here the ring formed by X, Y, Z, V and W

If, R ² is − (CH ₂ ) _n OR ⁸ or − (CH ₂ ) _n O (CH ₂ ) _n R ⁸ ; where R ² is independently 0-5 R. Is replaced by';
m and n are integers independently selected from 0 to 4;
p is an integer selected from 2-4;
Join

Each presence of is either a single bond or a double bond;
Each R ¹ is independently selected from halogen, -R, and -OR;
R ² is selected from: halogen, -R and-(CR ₂ ) _1-3- OR;
R ³ is selected from: -R and -CN;
R ⁴ and R ⁵ are independently −H or − (C1-C6) alkyl;
Each ^{R 6} is independently, -H or - be (C1 -C6) alkyl;
Each R ⁷ is independently -H or- (C1-C6) alkyl;
Each R ⁸ is independently a-(C1-C6) alkyl,-(C3-C10) -cycloalkyl, (C6-C10) -aryl, or 5- to 10-membered heteroaryl, where R ^{8 is.} Each existence of is independently replaced by 0-5 R';
Each R is independent:
H-,
(C1-C12) -aliphatic-,
(C3 to C10) -Cycloalkyl-,
(C3 to C10) -Cycloalkenyl-,
[(C3 to C10) -cycloalkyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkyl] -O- (C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl] -O- (C1 to C12) -aliphatic-,
(C6 to C10) -aryl-,
(C6 to C10) -aryl- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-O- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-N (R'')-(C1 to C12) aliphatic-,
Heterocyclyl of 3 to 10 members-,
(3-10 member heterocyclyl)-(C1-C12) Aliphatic-,
(3-10 member heterocyclyl) -O- (C1-C12) aliphatic-,
(3-10 member heterocyclyl) -N (R'')-(C1-C12) aliphatic-,
5-10 member heteroaryl-,
(5- to 10-membered heteroaryl)-(C1-C12) -aliphatic-,
(5-membered to 10-membered heteroaryl) -O- (C1-C12) -aliphatic-; and (5-membered to 10-membered heteroaryl) -N (R'')-(C1-C12) -aliphatic −
Selected from;
Here the heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO ₂ , and the heteroaryl is N, NH, O, And has 1 to 4 heteroatoms selected independently of S;
Where each existence of R is independently replaced by 0-5 R';
Alternatively, if two R groups are attached to the same atom, these two R groups, together with the atom to which they are attached, are N, NH, O, S, SO, and SO. It is possible to form a 3- to 10-membered aromatic or non-aromatic ring with 0 to 4 heteroatoms independently selected from _{2, where the ring is 0 to 5 Rs.} 'Is substituted as needed, and this ring is required for (C6-C10) aryl, 5-membered to 10-membered heteroaryl, (C3-C10) cycloalkyl, or 3-membered to 10-membered heterocyclyl. Condensed according to;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, -CH ₂ OR " _{, -CH 2} NR" ₂ , and -C (O) N (R'. ') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R') ₂ ;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl,-(C1-C6) -aryl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl. 5, 10-membered heteroaryl-, (C6-C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1) ~ C6) -alkyl-, (5-member to 10-membered heteroaryl) -O- (C1-C6) -alkyl-, and (C6-C10) -aryl-O- (C1-C6) -alkyl- And here each presence of R'' is: halogen, -R ^o , -OR ^o , oxo, -CH ₂ OR ^o , -CH ₂ N (R ^o ) ₂ , -C (O) N (R ^o ). _{^{2, -C (O) oR o}} , -NO 2, -NCS, -CN, -CF 3, independently with 0 to 5 substituents selected from -OCF _3, and -N ^(R _{o) 2} It is substituted Te, wherein each occurrence of ^{R o} is independently, - (C1 -C6) - aliphatic, (C3 -C6) - cycloalkyl, 3-6 membered heterocyclyl, 5- to 10-membered Heteroaryl-and (C6-C10) -aryl-are selected from.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式Ｉにおいて：
Ｕと、αおよびβによって表される２個の炭素原子とが一緒になって、０個〜２個の窒素原子を有する５員または６員の芳香環を形成し；
Ａは、Ｃ、ＣＲ^６、またはＮであり；
ＢおよびＦは各々独立して、Ｃ、ＣＲ^６、およびＮから選択され、ここでＢとＦとの両方がＮであることはできず；
Ｄは、Ｎ、ＮＲ^７、Ｏ、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｅは、Ｎ、ＮＲ^７、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｗは、Ｎ、ＮＲ^７、ＣＲ^６またはＣ（Ｒ^６）_２であり；
Ｘは、Ｎ、ＮＲ^７、Ｏ、ＣＲ^６またはＣ（Ｒ^６）_２であり；
ＹおよびＺは各々独立して、Ｃ、ＣＲ^６、およびＮから選択され、ここでＹとＺとの両方がＮであることはできず；
Ｖは、ＣまたはＣＲ^６であるか、
あるいはＺがＣまたはＣＲ^６である場合、Ｖは、Ｃ、ＣＲ^６、またはＮであり；
ここでＸ、Ｙ、Ｚ、ＶおよびＷによって形成される環が

である場合、Ｒ^２は、−（ＣＨ_２）_ｎＯＲ^８または−（ＣＨ_２）_ｎＯ（ＣＨ_２）_ｎＲ^８であり、ここでＲ^８の各存在は独立して、−（Ｃ１〜Ｃ６）アルキルまたは（Ｃ６〜Ｃ１０）−アリール（例えば、フェニル）であり、そしてＲ^２は独立して、０個〜５個のＲ’で置換されており；
ｍおよびｎは独立して、０〜４から選択される整数であり（いくつかの実施形態において、ｍは１であり）；
ｐは、２〜４から選択される整数であり；
結合

の各存在は、単結合または二重結合のいずれかであり；
各Ｒ^１は独立して、−Ｃｌ、−Ｆ、−ＯＭｅ、および−Ｃ≡ＣＨから選択され；
Ｒ^２は、ハロゲン、−（ＣＲ_２）_１〜３−ＯＲであり、ここでＲの各存在は独立して、−Ｈ、−（Ｃ１〜Ｃ６）アルキル、（Ｃ６〜Ｃ１０）−アリール−（例えば、フェニル）、および（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−（例えば、フェニル−（Ｃ１〜Ｃ６）アルキル−）から選択され、そしてＲの各存在は独立して、０個〜５個のＲ’で置換されており；
Ｒ^３は：−ＣＮ、−Ｃ≡ＣＨ、−Ｃ≡Ｃ−（Ｃ１〜Ｃ６）アルキル、−Ｃ≡Ｃ−フェニル、

から選択され、ここでＲ^３は、０個〜５個のＲ’で置換されており；
Ｒ^４およびＲ^５の各存在は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
各Ｒ^６は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
各Ｒ^７は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ_２ＯＲ’’、−ＣＨ_２ＮＲ’’_２、−Ｃ（Ｏ）Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ’’）_２から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、−（Ｃ１〜Ｃ６）−脂肪族、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択され、ここでＲ’’の各存在は：ハロゲン、−Ｒ^ｏ、−ＯＲ^ｏ、オキソ、−ＣＨ_２ＯＲ^ｏ、−ＣＨ_２ＮＲ^ｏ _２、−Ｃ（Ｏ）Ｎ（Ｒ^ｏ）_２、−Ｃ（Ｏ）ＯＲ^ｏ、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ^ｏ）_２から選択される０個〜５個の置換基で独立して置換されており、ここでＲ^ｏの各存在は独立して、−（Ｃ１〜Ｃ６）−脂肪族、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、および（Ｃ６〜Ｃ１０）−アリール−から選択される。
上記実施形態のうちのいくつかにおいて、Ｒ^３は：

から選択され、
ここでＲ’’の各存在は独立して、−（Ｃ１〜Ｃ６）−アルキル（例えば、直鎖または分枝状）、−Ｃ≡ＣＨ、フェニル、チオフェン、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−から選択され、ここで各Ｒ’’は、ハロゲン、−Ｒ^ｏ、−ＯＲ^ｏ、オキソ、−ＣＨ_２ＯＲ^ｏ、−ＣＨ_２ＮＲ^ｏ _２、−Ｃ（Ｏ）Ｎ（Ｒ^ｏ）_２、−Ｃ（Ｏ）ＯＲ^ｏ、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ^ｏ）_２から選択される０個〜３個の置換基で独立して置換されており、ここでＲ^ｏの各存在は独立して、−（Ｃ１〜Ｃ６）−脂肪族、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、および（Ｃ６〜Ｃ１０）−アリール−から選択される。 The present invention describes the formula I:

A compound of, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, provided in Formula I:
U and the two carbon atoms represented by α and β together form a 5- or 6-membered aromatic ring with 0 to 2 nitrogen atoms;
A is C, CR ⁶ , or N;
B and F are independently ^{selected from C, CR 6} , and N, where both B and F cannot be N;
D is N, NR ⁷ , O, CR ⁶ or C (R ⁶ ) ₂ ;
E is N, NR ⁷ , CR ⁶ or C (R ⁶ ) ₂ ;
W is N, NR ⁷ , CR ⁶ or C (R ⁶ ) ₂ ;
X is N, NR ⁷ , O, CR ⁶ or C (R ⁶ ) ₂ ;
Y and Z are independently ^{selected from C, CR 6} , and N, where both Y and Z cannot be N;
V is C or CR ⁶ or
Alternatively, if Z is C or CR ⁶ , then V is C, CR ⁶ , or N;
Here the ring formed by X, Y, Z, V and W

If, R ² is − (CH ₂ ) _n OR ⁸ or − (CH ₂ ) _n O (CH ₂ ) _n R ⁸ , where ^{each presence of R 8} is independent, − (C1 to C6) alkyl or (C6-C10) - aryl (e.g., phenyl), and ^{R 2} are independently is substituted with 0 to five R ';
m and n are independently integers selected from 0 to 4 (in some embodiments, m is 1);
p is an integer selected from 2-4;
Join

Each presence of is either a single bond or a double bond;
Each R ¹ is independently selected from -Cl, -F, -OMe, and -C≡CH;
R ² is a halogen, − (CR ₂ ) _1-3 −OR, where each presence of R is independently −H, − (C1-C6) alkyl, (C6-C10) -aryl-( For example, phenyl), and (C6-C10) -aryl- (C1-C12) aliphatic- (eg, phenyl- (C1-C6) alkyl-), and each presence of R is independently 0. Replaced by 5 to 5 R';
R ³ is: -CN, -C≡CH, -C≡C- (C1-C6) alkyl, -C≡C-phenyl,

Selected from, where R ³ is replaced by 0-5 R';
Each presence of R ⁴ and R ⁵ is independently -H or- (C1-C6) alkyl;
Each ^{R 6} is independently, -H or - be (C1 -C6) alkyl;
Each R ⁷ is independently -H or- (C1-C6) alkyl;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, -CH ₂ OR " _{, -CH 2} NR" ₂ , and -C (O) N (R'. ') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R') ₂ ;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl,-(C1-C6) -aryl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl. 5, 10-membered heteroaryl-, (C6-C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1) ~ C6) -alkyl-, (5-member to 10-membered heteroaryl) -O- (C1-C6) -alkyl-, and (C6-C10) -aryl-O- (C1-C6) -alkyl- And where each presence of R'' is: halogen, -R ^o , -OR ^o , oxo, -CH ₂ OR ^o , -CH ₂ NR ^o ₂ , -C (O) N (R ^o ) ₂ ,- Independently substituted with 0-5 substituents selected from C (O) OR ^o , -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R ^o ) _2. and, wherein each occurrence of ^{R o} is independently, - (C1 -C6) - aliphatic, (C3 -C6) - cycloalkyl, 3-6 membered heterocyclyl, 5- to 10-membered heteroaryl -, And (C6 to C10) -aryl- are selected.
In some of the above embodiments, R ³ is:

Selected from
Here, each presence of R'' is independent of-(C1-C6) -alkyl (eg, linear or branched), -C≡CH, phenyl, thiophene, (5- to 10-membered heteroaryl). )-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1-C6) -alkyl-where each R'' is halogen, -R ^o , -OR ^o , oxo. , -CH ₂ OR ^o , -CH ₂ NR ^o ₂ , -C (O) N (R ^o ) ₂ , -C (O) OR ^o , -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N ^(R _o) are independently substituted with 0-3 substituents selected from _2, wherein each occurrence of ^{R o} is independently, - (C1 -C6) - fat It is selected from the group, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-, and (C6-C10) -aryl-.

In some embodiments of the compounds of formula I, X, Y, Z, V and W together form a five-membered aromatic or non-aromatic ring with 1 to 4 nitrogen atoms. wherein said ring is substituted with 0-3 ^{R 6,} and 0-2 ^{R 7.} In some embodiments, X, Y, Z, V and W together form a 5-membered aromatic ring with 1 to 3 nitrogen atoms, where the ring is 0. It substituted with pieces to 2 pieces of ^{R 6} and 0 to 1 amino ^{R 7.}

から選択される環を形成する。 In certain embodiments, X, Y, Z, V and W are:

Form a ring selected from.

から選択される環を形成する。 In some embodiments, X, Y, Z, V and W are:

Form a ring selected from.

から選択される環を形成する。 In some embodiments of the compounds of formula I, W is N. In some embodiments, W is N, and X, Y, Z, V and W are:

Form a ring selected from.

から選択される環を形成する。 In some embodiments, W is N, and X, Y, Z, V and W are:

Form a ring selected from.

である。 In certain embodiments of the compounds of formula I, the rings formed by X, Y, Z, V and W are:

Is.

である。 In certain embodiments of the compounds of formula I, the rings formed by X, Y, Z, V and W are:

Is.

から選択される。 In certain embodiments of the compounds of formula I, the rings formed by X, Y, Z, V and W are:

Is selected from.

から選択される。いくつかの実施形態において、Ｘ、Ｙ、Ｚ、ＶおよびＷによって形成される環は：

である。いくつかの実施形態において、Ｘ、Ｙ、Ｚ、ＶおよびＷによって形成される環は：

である。 In certain embodiments of the compounds of formula I, the rings formed by X, Y, Z, V and W are:

Is selected from. In some embodiments, the rings formed by X, Y, Z, V and W are:

Is. In some embodiments, the rings formed by X, Y, Z, V and W are:

Is.

In some embodiments of the compounds of formula I, A, B, D, E and F together form a 5-membered aromatic or non-aromatic ring with 1 to 4 nitrogen atoms. wherein said ring is substituted with 0-3 ^{R 6,} and 0-2 ^{R 7.} In certain embodiments, A, B, D, E and F together form a 5-membered aromatic ring with 1 to 3 nitrogen atoms, where the ring is 0. It substituted with pieces to 2 pieces of ^{R 6} and 0 to 1 amino ^{R 7.}

から選択される環を形成する。 In some embodiments of the compounds of formula I, A, B, D, E and F are:

Form a ring selected from.

である。 In certain embodiments of the compounds of formula I, the rings formed by A, B, D, F and E are:

Is.

もしくはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体または組み合わせの構造を有し、式中、ｍ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６は、式Ｉにおいて定義されたとおりである。 In some embodiments of a compound of formula I, the compound is of formula II :.

Alternatively, it has a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination structure in the formulas m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ And R ⁶ are as defined in Formula I.

もしくはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体または組み合わせの構造を有し、式中、ｍ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６は、式Ｉにおいて定義されたとおりである。 In some embodiments of a compound of formula I, the compound is of formula III :.

Alternatively, it has a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination structure in the formulas m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ And R ⁶ are as defined in Formula I.

もしくはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体または組み合わせの構造を有し、式中、Ｒ^２は、−ＯＲ^８、−ＳＲ^８または−（ＣＨ_２）_ｎＯＲ^８であり、Ｒ^２は、独立して、０個〜５個のＲ’で置換されており、ｍ、ｎ、Ｒ^１、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６およびＲ^８は、式Ｉにおいて定義されたとおりである。いくつかの実施形態において、Ｒ^２は、−ＯＲ^８である。いくつかの実施形態において、Ｒ^２は、−（ＣＨ_２）_ｎＯＲ^８である。 In some embodiments of a compound of formula I, the compound is of formula IV :.

Alternatively, it has a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination structure, wherein R ² is -OR ⁸ , -SR ⁸ or-(CH _2). ) _N OR ⁸ , where R ² is independently substituted with 0-5 R', m, n, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁸ Is as defined in Formula I. In some embodiments, R ² is −OR ⁸ . In some embodiments, R ² is − (CH ₂ ) _n OR ⁸ .

もしくはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体または組み合わせの構造を有し、式中、Ｒ^２は、−（ＣＨ_２）_ｎＯ（ＣＨ_２）_ｎＲ^８、−（ＣＨ_２）_ｐＲ^８または−（ＣＨ_２）_ｎＮ（Ｒ’’）Ｒ^１０であり、Ｒ^２は、独立して、０個〜５個のＲ’で置換されており、ｍ、ｎ、ｐ、Ｒ^１、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^８、Ｒ^１０およびＲ’’は、本明細書中に定義されるとおりである。いくつかの実施形態において、Ｒ^２は、−（ＣＨ_２）_ｎＯ（ＣＨ_２）_ｎＲ^８である。 In some embodiments of a compound of formula I, the compound is of formula IV :.

Alternatively, it has a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination structure, wherein R ² is − (CH ₂ ) _n O (CH ₂ ) _n. R ⁸ ,-(CH ₂ ) _p R ⁸ or-(CH ₂ ) _n N (R'') R ¹⁰ , where R ² is independently replaced by 0-5 R'. , M, n, p, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹⁰ and R'' as defined herein. In some embodiments, R ² is − (CH ₂ ) _n O (CH ₂ ) _n R ⁸ .

In some embodiments of compounds of formula I, II, III or IV, ^{each presence of R 1} is halogen, -R, -OR, -NO ₂ , -CN, -CF ₃ , -OCF ₃ , -N. Selected from (R) ₂ and -N (R) SO ₂ R, where each presence of R is independently substituted with 0-5 R'. In some embodiments, ^{each presence of R 1} independently comprises a halogen, —H, − (C1-C6) alkyl, −OH, —O ((C1-C6) alkyl), −NO ₂ , −. CN, -CF ₃ , -OCF ₃ , -NH ₂ , -N ((C1-C6) alkyl) ₂ , -N ((C1-C6) alkyl) SO ₂ ((C1-C6) alkyl) and -NHSO ₂ ((C1-C6) alkyl), where the alkyl is independently substituted with 0-5 R'. In certain embodiments, ^{each presence of R 1} independently has -H, -F, -Cl, -Br, -OH, -Me, -Et, -OME, -OEt, -NO ₂ , -. It is selected from CN, -CF ₃ , -OCF ₃ , -NH ₂ , -NMe ₂ , -NEt ₂ , -NHSO ₂ Me and -NHSO ₂ Et. In certain embodiments of any one compound of formulas I-IV, at least one R ¹ is −OR. In some embodiments, the at least one R ¹ is —O ((C1-C6) alkyl), eg, —OMe.

In some embodiments of compounds of formula I, II or III, R ² is a halogen, −R, −OR, −NO ₂ , − (CR ₂ ) _1-3 R, − (CR ₂ ) _1-3. Selected from -OR, -CN, -CF ₃ , -C (O) NR ₂ , -C (O) OR and -OCF ₃ , where each presence of R is 0-5 independently. Is replaced by R'. In some embodiments, R ² is:
-H,-(C1-C6) alkyl, -CH _2- O ((C1-C6) alkyl),-(C ((C1-C6) alkyl) ₂ ) _1-3- O ((C1-C6) alkyl) ), -OH, -O ((C1-C6) alkyl), -NO ₂ , -CN, -CF ₃ , -OCF ₃ , (C3 to C10) -cycloalkyl-,
-C (O) N ((C1 to C6) alkyl) ₂ , -C (O) O ((C1 to C6) alkyl), 3 to 10 member heterocyclyl-,
(C6 to C10) Aryl-, 5- to 10-membered heteroaryl-,
(C6 to C10) aryl- (C1 to C12) aliphatic-,
(C6 to C10) Aryl-O- (C1 to C12) Aliphatic-,
(C6 to C10) Aryl-N (R'')-(C1 to C12) Aliphatic-, (C6 to C10) Aryl- (C1 to C12) Aliphatic-O-,
(5- to 10-membered heteroaryl)-(C1-C12) -aliphatic-,
(5- to 10-membered heteroaryl) -O- (C1-C12) -aliphatic-,
(5- to 10-membered heteroaryl) -N (R'')-(C1-C12) -aliphatic-,
(5- to 10-membered heteroaryl)-(C1-C12) -aliphatic-O-,
(3-10 member heterocyclyl)-(C1-C12) Aliphatic-,
(3-10 member heterocyclyl) -O- (C1-C12) aliphatic-,
(3-10 member heterocyclyl) -N (R'')-(C1-C12) aliphatic-and (3-10 member heterocyclyl)-(C1-C12) aliphatic-O-
Selected from, where R ² is independently substituted with 0-5 R'.

In some embodiments of the compounds of formula I, II or III, ^{R 2} is, -H, -Me, -Et, propyl, isopropyl, butyl, tert- butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CF ₃ , -C (O) OMe, -C (O) OEt, -OME, -CH ₂ OMe, -CH ₂ OEt, -CH ₂ OPh, -CH ₂ -pyrrolidin, -CH ₂ -morpholine, -CH _2- Selected from pyridine and -CH ₂ Ph, where R ² is substituted with 0 to 3 R'. In some embodiments of compounds of formula I, II or III, R ² is -R'', -OR'', oxo, -CH ₂ OR'', -CH ₂ NR'' ₂ , -C ( O) N (R'') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R'') ₂ selected from 0 -Me substituted with 3 to 3 R'where R'' is independently H,-(C1-C6) -alkyl, (C6-C10) -aryl- and (C6). It is selected from ~ C10) -aryl- (C1-C6) -alkyl-. In some embodiments, R ² is independent of 0 to 3 R'selected from -N (Me) ₂ , -N (Et) ₂ and -N (Me) (CH _{2 Ph).} Replaced by -Me.

In some embodiments of compounds of formula I, II or III, R ² is -CH ₂ Ph, -CH ₂ CH ₂ Ph, -Ph, -OCH ₂ Ph, -CH ₂ OPh, -OCH ₂ CH _2. It is selected from Ph, -CH ₂ CH ₂ OPh, -CH ₂ -pyrrolidin, -CH ₂ -morpholine, -CH ₂ -pyridine and -CH ₂ Ph, where the Ph, pyrrolidine, pyridine or morpholine is zero. It is replaced with ~ 5 R'. In some embodiments of compounds of formula I, II or III, R ² is -CH ₂ Ph, -CH ₂ CH ₂ Ph, -Ph, -OCH ₂ Ph, -CH ₂ OPh, -OCH ₂ CH _2. It is selected from Ph, -CH ₂ CH ₂ OPh, -CH ₂ -pyrrolidin, -CH ₂ -morpholin, -CH ₂ -pyridine and -CH ₂ Ph, wherein the Ph, pyrrolidine, pyridine or morpholin is a halogen. (C1 -C6) - alkyl, -OH, -O ((C1~C6) - _{alkyl), - CH 2 OH, -CH} 2 O (C1~C6) - _{alkyl), - CH 2 N (C1~C6} ) -Alkyl) ₂ , -C (O) O (C1-C6) -alkyl), -C (O) N (C1-C6) -alkyl) ₂ , -NO ₂ , -CN, -CF ₃ , -OCF ₃ And -N (C1-C6) -alkyl) Substituted with 0-5 R'selected independently of _2. In some of the above embodiments 0, the ^{R 2} -Ph, pyrrolidine, pyridine or morpholine, to -F, -Cl, -CN, -Me, -Et, is independently selected from -OMe and -OEt It is replaced with 5 to 5 R's. In some embodiments of compounds of formula I, II or III, R ² is -CH ₂ Ph, -CH ₂ OPh, -CH ₂ -pyridine, -CH ₂ -pyrrolidin or -CH ₂ -morpholine. Here, the -Ph, pyrrolidine, pyridine or morpholine is replaced with 0 to 3 R'independently selected from -F, -Cl, -CN, -Me and -OMe.

In some embodiments of the compounds of formula IV, R ² is −OR ⁸ , −SR ⁸ , − (CH ₂ ) _n OR ⁸ , − (CH ₂ ) _n O (CH ₂ ) _n R ⁸ , − ( CH ₂ ) _p R ⁸ or-(CH ₂ ) _n N (R'') R ¹⁰ , where each R ⁸ is independently -(C1-C6) alkyl,-(C3 to C10). - cycloalkyl, (C6-C10) - aryl or 5-10 membered heteroaryl, each occurrence of ^{R 8} is independently is substituted with 0 to five R '; n is An integer selected from 0 to 4; p is an integer selected from 2 to 4; each R ¹⁰ is independently a-(C3 to C10) -cycloalkyl, 3 to 10 membered heterocyclyl. -, (C6-C10) -aryl or 5-10 membered heteroaryl ^{, each presence of R 10} is independently substituted with 0-5 R'. In some embodiments, R ² is OR ⁸ . In some embodiments, R ² is OR ⁸ , where R ⁸ is (C6-C10) -aryl substituted with 0-5 R'. In some embodiments, R ² is OR ⁸ , where R ⁸ is (C6-C10) -aryl substituted with 0 to 3 halogens (eg, -F). In some embodiments, R ² is − (CH ₂ ) _n OR ⁸ or − (CH ₂ ) _n O (CH ₂ ) _n R ⁸ . In some embodiments, R ² is − (CH ₂ ) _n OR ⁸ or − (CH ₂ ) _n O (CH ₂ ) _n R ⁸ , where R ⁸ is − (C1 to C6). alkyl, (C6-C10) - aryl or 5-10 membered heteroaryl, each occurrence of ^{R 8} is independently substituted with 0 to five R '.

から選択され、ここで、Ｒ^９は、−Ｈ、−Ｍｅ、−Ｅｔ、−ＣＦ_３、イソプロピル、−ＯＭｅ、−ＯＥｔ、−Ｏ−イソプロピル、−ＣＨ_２ＮＭｅ_２、−ｔｅｒｔ−ブチルおよびシクロプロピルから選択される。 In some embodiments of compounds of formula I, II, III or IV, R ³ is a halogen, -R, -CN, -CF ₃ , -SO ₂ R, -C (O) N (R) ₂ , Selected from −C (O) R and −C (O) OR, where each presence of R is independently substituted with 0-5 R'. In some embodiments, R ³ is -F, -Br, -Cl,-(C1-C6) alkyl, -CN, -C≡C, -CF ₃ , -SO ₂ ((C1-C6) alkyl. ), -C (O) N ((C1 to C6) alkyl) ₂ , -C (O) NH ₂ , -C (O) ((C1 to C6) alkyl), -SO ₂ ((C6 to C10)- Aryl), -C (O) O ((C1-C6) alkyl),-(C2-C6) -alkenyl,-(C2-C6) -alkynyl,-(C6-C10) -aryl, 5-10 members Heteroaryl-selected from 3-10 membered heterocyclyl-where the alkyl, alkenyl, alkynyl, aryl, heteroaryl or heterocyclyl-are independently substituted with 0-5 R'. There is. Formula I, II, in some embodiments of the compounds of the III or ^IV, R 3 is, -H, -C (O) OMe , -C (O) Et, -C (O) NMe 2, -C ( O) NH ₂ , -C (O) OEt, -C (O) OCH ₂ (tert-butyl), -C (O) OCH ₂ CF ₃ , -C (O) O (isopropyl), -C (O) NEt ₂ , -CHF ₂ , -CN, -C≡C, -SO ₂ Me, -SO ₂ Et, -SO ₂ Ph (Me), -CF ₃ , -CHF ₂ , -Me, -Et, -Br, -Cl, -CH ₂ Ph,

It is selected from, where, ^{R 9} is, -H, -Me, -Et, -CF _3, isopropyl, -OMe, -OEt, -O- _isopropyl, -CH ₂ NMe 2,-tert-butyl and cyclopropyl Is selected from.

であり、ここで、Ｒ^９は、−Ｈ、−Ｍｅ、−Ｅｔ、−ＣＦ_３、イソプロピル、−ＯＭｅ、−ＯＥｔ、−Ｏ−イソプロピル、−ＣＨ_２ＮＭｅ_２、−ｔｅｒｔ−ブチルおよびシクロプロピルから選択される。 Formula I, II, in certain embodiments of compounds of III or IV, ^{R 3} is -C (O) OMe or -C (O) OEt. Formula I, II, in certain embodiments of compounds of III or IV, ^{R 3} is

Where R ⁹ is from -H, -Me, -Et, -CF ₃ , isopropyl, -OME, -OEt, -O-isopropyl, -CH ₂ NMe ₂ , -tert-butyl and cyclopropyl. Be selected.

Formula I, II, in some embodiments of the compounds of the III or IV, ^{R 4} and ^{R 5} are each independently, -H, selected from halogen and -R, wherein each occurrence of R is Independently substituted with 0-5 R', or R ⁴ and R ⁵ together with the carbon atom to which they are attached, N, O, S, SO and SO ₂ Can form 3-10 membered aromatic or non-aromatic rings with 0-3 additional heteroatoms selected independently from, where the rings are 0-5 R'. It has been replaced. In some embodiments, R ⁴ and R ⁵ are independently selected from -H, -Me, -Et, -F, or R ⁴ and R ⁵ are bound to each other. Together with the carbon atom, it forms a 3- to 8-membered aliphatic ring. In certain embodiments, R ⁴ and R ⁵ are both H.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式ＩＩにおいて：
ｍは、０〜３であり（例えば、ｍは１であり）；
各Ｒ^１は独立して、−Ｃｌ、−Ｆ、−ＯＭｅ、および−Ｃ≡ＣＨから選択され；
Ｒ^２は、ハロゲンまたは−（ＣＲ_２）_１〜３−ＯＲであり、ここでＲの各存在は独立して、−Ｈ、−（Ｃ１〜Ｃ６）アルキル、（Ｃ６〜Ｃ１０）−アリール−（例えば、フェニル）、および（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−（例えば、フェニル−（Ｃ１〜Ｃ６）アルキル−）から選択され、そしてＲの各存在は独立して、０個〜５個のＲ’で置換されており；
Ｒ^３は：−ＣＮ、−Ｃ≡ＣＨ、−Ｃ≡Ｃ−（Ｃ１〜Ｃ６）アルキル、−Ｃ≡Ｃ−フェニル、

から選択され、ここでＲ^３は、０個〜５個のＲ’で置換されており；
Ｒ^４およびＲ^５の各存在は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
各Ｒ^６は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ_２ＯＲ’’、−ＣＨ_２ＮＲ’’_２、−Ｃ（Ｏ）Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ’’）_２から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、−（Ｃ１〜Ｃ６）−脂肪族、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、または（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択され、ここでＲ’’の各存在は：ハロゲン、−Ｒ^ｏ、−ＯＲ^ｏ、オキソ、−ＣＨ_２ＯＲ^ｏ、−ＣＨ_２Ｎ（Ｒ^ｏ）_２、−Ｃ（Ｏ）Ｎ（Ｒ^ｏ）_２、−Ｃ（Ｏ）ＯＲ^ｏ、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ^ｏ）_２から選択される０個〜５個の置換基で独立して置換されており、ここでＲ^ｏの各存在は独立して、−（Ｃ１〜Ｃ６）−脂肪族、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、および（Ｃ６〜Ｃ１０）−アリール−から選択される。
上記実施形態のうちのいくつかにおいて、Ｒ^３は：

から選択され、
ここでＲ’’の各存在は独立して、−（Ｃ１〜Ｃ６）−アルキル（例えば、直鎖または分枝状）、−Ｃ≡ＣＨ、フェニル、チオフェン、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−から選択され、ここで各Ｒ’’は、ハロゲン、−Ｒ^ｏ、−ＯＲ^ｏ、オキソ、−ＣＨ_２ＯＲ^ｏ、−ＣＨ_２Ｎ（Ｒ^ｏ）_２、−Ｃ（Ｏ）Ｎ（Ｒ^ｏ）_２、−Ｃ（Ｏ）ＯＲ^ｏ、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ^ｏ）_２から選択される０個〜３個の置換基で独立して置換されており、ここでＲ^ｏの各存在は独立して、−（Ｃ１〜Ｃ６）−脂肪族、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、および（Ｃ６〜Ｃ１０）−アリール−から選択される。 In some embodiments, the present invention relates to Formula II :.

A compound of, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, provided in Formula II:
m is 0 to 3 (for example, m is 1);
Each R ¹ is independently selected from -Cl, -F, -OMe, and -C≡CH;
R ² is halogen _{or-(CR 2} ) _1-3- OR, where each presence of R is independently -H,-(C1-C6) alkyl, (C6-C10) -aryl-( For example, phenyl), and (C6-C10) -aryl- (C1-C12) aliphatic- (eg, phenyl- (C1-C6) alkyl-), and each presence of R is independently 0. Replaced by 5 to 5 R';
R ³ is: -CN, -C≡CH, -C≡C- (C1-C6) alkyl, -C≡C-phenyl,

Selected from, where R ³ is replaced by 0-5 R';
Each presence of R ⁴ and R ⁵ is independently -H or- (C1-C6) alkyl;
Each ^{R 6} is independently, -H or - be (C1 -C6) alkyl;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, -CH ₂ OR " _{, -CH 2} NR" ₂ , and -C (O) N (R'. ') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R') ₂ ;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl,-(C1-C6) -aryl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl. 5, 10-membered heteroaryl-, (C6-C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1) ~ C6) -alkyl-, (5-member to 10-membered heteroaryl) -O- (C1-C6) -alkyl-, or (C6-C10) -aryl-O- (C1-C6) -alkyl- And here each presence of R'' is: halogen, -R ^o , -OR ^o , oxo, -CH ₂ OR ^o , -CH ₂ N (R ^o ) ₂ , -C (O) N (R ^o ). _{^{2, -C (O) oR o}} , -NO 2, -NCS, -CN, -CF 3, independently with 0 to 5 substituents selected from -OCF _3, and -N ^(R _{o) 2} It is substituted Te, wherein each occurrence of ^{R o} is independently, - (C1 -C6) - aliphatic, (C3 -C6) - cycloalkyl, 3-6 membered heterocyclyl, 5- to 10-membered Heteroaryl-and (C6-C10) -aryl-are selected from.
In some of the above embodiments, R ³ is:

Selected from
Here, each presence of R'' is independent of-(C1-C6) -alkyl (eg, linear or branched), -C≡CH, phenyl, thiophene, (5- to 10-membered heteroaryl). )-(C1-C6) -alkyl-, and (C6-C10) -aryl- (C1-C6) -alkyl-where each R'' is halogen, -R ^o , -OR ^o,. Oxo, -CH ₂ OR ^o , -CH ₂ N (R ^o ) ₂ , -C (O) N (R ^o ) ₂ , -C (O) OR ^o , -NO ₂ , -NCS, -CN, -CF _3, -OCF _3, and -N ^(R _o) are independently substituted with 0-3 substituents selected from _2, wherein each occurrence of ^{R o} is independently, - (C1 to It is selected from C6) -aliphatic, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-, and (C6-C10) -aryl-.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式ＩＩにおいて：
ｍは、０〜３であり；
各Ｒ^１は独立して、ハロゲン（例えば、Ｃｌ、Ｆ）、−Ｈ、−（Ｃ１〜Ｃ６）アルキル、−ＯＨ、−Ｏ（（Ｃ１〜Ｃ６）アルキル）（例えば、−ＯＭｅ）、−ＮＯ_２、−ＣＮ、−ＣＦ_３、および−ＯＣＦ_３から選択され、ここでＲ^１は独立して、０個〜５個のＲ’で置換されており；
Ｒ^２は：
−Ｈ、ハロゲン、−（Ｃ１〜Ｃ６）アルキル、−ＯＨ、−Ｏ（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）Ｏ（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）ＮＲ_２、
（Ｃ６〜Ｃ１０）−アリール−（例えば、フェニル）、
（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ１２）脂肪族−、
（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（５員〜１０員のヘテロアリール）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、および
（３員〜１０員のヘテロシクリル）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−
から選択され、
ここでＲ^２は独立して、０個〜５個のＲ’で置換されており；
Ｒ^３は：
−（Ｃ１〜Ｃ６）アルキル、−（Ｃ２〜Ｃ６）アルケニル（例えば、−ＣＨ＝ＣＨ_２）、−Ｃ≡ＣＨ、−ＣＮ、ハロゲン（例えば、Ｂｒ）、−ＳＯ_２（（Ｃ６〜Ｃ１０）−アリール）、−ＳＯ_２（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）Ｎ（（Ｃ１〜Ｃ６）アルキル）_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｏ（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）（（Ｃ１〜Ｃ６）アルキル）、−（Ｃ６〜Ｃ１０）アリール、５員〜１０員のヘテロアリール（例えば、５員のヘテロアリール、例えば、必要に応じて置換された

）、および５員〜１０員のヘテロシクリル（例えば、５員のヘテロシクリル、例えば、必要に応じて置換された

）から選択され、ここでＲ^３は独立して、０個〜５個のＲ’で置換されており；
Ｒ^４およびＲ^５は各々独立して、−Ｈ、ハロゲンおよび−（Ｃ１〜Ｃ６）アルキルから選択され；
Ｒ^６は、−Ｈおよび−（Ｃ１〜Ｃ６）アルキルから選択され；
各Ｒは独立して：
Ｈ−、
（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ３〜Ｃ１０）−シクロアルキル−、
（Ｃ３〜Ｃ１０）−シクロアルケニル−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−、
（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
３員〜１０員のヘテロシクリル−、
（３員〜１０員のヘテロシクリル）−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
５員〜１０員のヘテロアリール−、
（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ１２）−脂肪族−、
（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−；および
（５員〜１０員のヘテロアリール）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）−脂肪族−
から選択され；
ここでこのヘテロシクリルは、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される１個〜４個のヘテロ原子を有し、そしてこのヘテロアリールは、Ｎ、ＮＨ、Ｏ、およびＳから独立して選択される１個〜４個のヘテロ原子を有し；
ここでＲの各存在は独立して、０個〜５個のＲ’で置換されているか；
あるいは２個のＲ基が同じ原子に結合している場合、これらの２個のＲ基は、これらが結合している原子と一緒になって、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される０個〜４個のヘテロ原子を有する３員〜１０員の芳香族または非芳香族の環を形成し得、ここでこの環は、０個〜５個のＲ’で必要に応じて置換されており、そしてこの環は、（Ｃ６〜Ｃ１０）アリール、５員〜１０員のヘテロアリール、（Ｃ３〜Ｃ１０）シクロアルキル、または３員〜１０員のヘテロシクリルに必要に応じて縮合しており；
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ_２ＯＲ’’、−ＣＨ_２ＮＲ’’_２、−Ｃ（Ｏ）Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ’’）_２から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択される。 In some embodiments, the present invention relates to Formula II :.

A compound of, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, provided in Formula II:
m is 0 to 3;
Each R ¹ independently has a halogen (eg, Cl, F), -H,-(C1-C6) alkyl, -OH, -O ((C1-C6) alkyl) (eg, -OME), -NO. _{Selected from 2} , -CN, -CF ₃ , and -OCF ₃ , where R ¹ is independently substituted with 0-5 R';
R ² is:
-H, Halogen,-(C1-C6) alkyl, -OH, -O ((C1-C6) alkyl), -C (O) O ((C1-C6) alkyl), -C (O) NR ₂ ,
(C6 to C10) -aryl- (eg, phenyl),
(C6 to C10) -aryl- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-O- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-N (R'')-(C1 to C12) aliphatic-,
(5- to 10-membered heteroaryl)-(C1-C12) aliphatic-,
(5- to 10-membered heteroaryl) -O- (C1-C12) aliphatic-,
(5- to 10-membered heteroaryl) -N (R'')-(C1-C12) aliphatic-,
(3-10 member heterocyclyl)-(C1-C12) Aliphatic-,
(3-10 member heterocyclyl) -O- (C1-C12) aliphatic-and (3-10 member heterocyclyl) -N (R'')-(C1-C12) aliphatic-
Selected from
Here R ² is independently replaced by 0-5 R';
R ³ is:
-(C1-C6) alkyl,-(C2-C6) alkenyl (eg-CH = CH ₂ ), -C≡CH, -CN, halogen (eg Br), -SO ₂ ((C6-C10)- Aryl), -SO _{2 (} (C1-C6) alkyl), -C (O) N ((C1-C6) alkyl) ₂ , -C (O) NH ₂ , -C (O) O ((C1-C6) ) Alkyl), -C (O) ((C1-C6) alkyl),-(C6-C10) aryl, 5-membered to 10-membered heteroaryl (eg, 5-membered heteroaryl, eg, substituted as needed) Was done

), And 5-member to 10-membered heterocyclyls (eg, 5-membered heterocyclyls, eg, substituted as needed).

), Where R ³ is independently replaced by 0-5 R';
R ⁴ and R ⁵ are independently selected from -H, halogen and-(C1-C6) alkyl;
R ⁶ is, -H and - is selected from (C1 -C6) alkyl;
Each R is independent:
H-,
(C1-C12) -aliphatic-,
(C3 to C10) -Cycloalkyl-,
(C3 to C10) -Cycloalkenyl-,
[(C3 to C10) -cycloalkyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkyl] -O- (C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl] -O- (C1 to C12) -aliphatic-,
(C6 to C10) -aryl-,
(C6 to C10) -aryl- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-O- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-N (R'')-(C1 to C12) aliphatic-,
Heterocyclyl of 3 to 10 members-,
(3-10 member heterocyclyl)-(C1-C12) Aliphatic-,
(3-10 member heterocyclyl) -O- (C1-C12) aliphatic-,
(3-10 member heterocyclyl) -N (R'')-(C1-C12) aliphatic-,
5-10 member heteroaryl-,
(5- to 10-membered heteroaryl)-(C1-C12) -aliphatic-,
(5-membered to 10-membered heteroaryl) -O- (C1-C12) -aliphatic-; and (5-membered to 10-membered heteroaryl) -N (R'')-(C1-C12) -aliphatic −
Selected from;
Here the heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO ₂ , and the heteroaryl is N, NH, O, And has 1 to 4 heteroatoms selected independently of S;
Where each existence of R is independently replaced by 0-5 R';
Alternatively, if two R groups are attached to the same atom, these two R groups, together with the atom to which they are attached, are N, NH, O, S, SO, and SO. It is possible to form a 3- to 10-membered aromatic or non-aromatic ring with 0 to 4 heteroatoms independently selected from _{2, where the ring is 0 to 5 Rs.} 'Is substituted as needed, and this ring is required for (C6-C10) aryl, 5-membered to 10-membered heteroaryl, (C3-C10) cycloalkyl, or 3-membered to 10-membered heterocyclyl. Condensed according to;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, -CH ₂ OR " _{, -CH 2} NR" ₂ , and -C (O) N (R'. ') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R') ₂ ;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-. , (C6 to C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1-C6) -alkyl-, (5-membered) It is selected from 10-membered heteroaryl) -O- (C1-C6) -alkyl- and (C6-C10) -aryl-O- (C1-C6) -alkyl-.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式ＩＩにおいて：
ｍは、０〜３であり；
各Ｒ^１は独立して、ハロゲン（例えば、Ｃｌ、Ｆ）、−Ｈ、−（Ｃ１〜Ｃ６）アルキル、−ＯＨ、−Ｏ（（Ｃ１〜Ｃ６）アルキル）（例えば、−ＯＭｅ）、−ＮＯ_２、−ＣＮ、−ＣＦ_３、および−ＯＣＦ_３から選択され、ここでＲ^１は独立して、０個〜５個のＲ’で置換されており；
Ｒ^２は：
−Ｈ、−Ｃ（Ｏ）ＮＲ_２、および（Ｃ６〜Ｃ１０）−アリール−（例えば、フェニル）から選択され；
Ｒ^３は：
−（Ｃ１〜Ｃ６）アルキル、−（Ｃ２〜Ｃ６）アルケニル（例えば、−ＣＨ＝ＣＨ_２）、−Ｃ≡ＣＨ、−ＣＮ、ハロゲン（例えば、Ｂｒ）、−ＳＯ_２（（Ｃ６〜Ｃ１０）−アリール）、−ＳＯ_２（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）Ｎ（（Ｃ１〜Ｃ６）アルキル）_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｏ（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）（（Ｃ１〜Ｃ６）アルキル）、−（Ｃ６〜Ｃ１０）アリール、５員〜１０員のヘテロアリール（例えば、５員のヘテロアリール、例えば、必要に応じて置換された

）、および５員〜１０員のヘテロシクリル（例えば、５員のヘテロシクリル、例えば、必要に応じて置換された

）から選択され、ここでＲ^３は独立して、０個〜５個のＲ’で置換されており；
Ｒ^４およびＲ^５は各々、−Ｈ、ハロゲンおよび−（Ｃ１〜Ｃ６）アルキルであり；
Ｒ^６は、−Ｈおよび−（Ｃ１〜Ｃ６）アルキルから選択され；
各Ｒは独立して：
Ｈ−、
（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ３〜Ｃ１０）−シクロアルキル−、
（Ｃ３〜Ｃ１０）−シクロアルケニル−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−、
（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
３員〜１０員のヘテロシクリル−、
（３員〜１０員のヘテロシクリル）−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
５員〜１０員のヘテロアリール−、
（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ１２）−脂肪族−、
（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−；および
（５員〜１０員のヘテロアリール）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）−脂肪族−
から選択され；
ここでこのヘテロシクリルは、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される１個〜４個のヘテロ原子を有し、そしてこのヘテロアリールは、Ｎ、ＮＨ、Ｏ、およびＳから独立して選択される１個〜４個のヘテロ原子を有し；
ここでＲの各存在は独立して、０個〜５個のＲ’で置換されているか；
あるいは２個のＲ基が同じ原子に結合している場合、これらの２個のＲ基は、これらが結合している原子と一緒になって、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される０個〜４個のヘテロ原子を有する３員〜１０員の芳香族または非芳香族の環を形成し得、ここでこの環は、０個〜５個のＲ’で必要に応じて置換されており、そしてこの環は、（Ｃ６〜Ｃ１０）アリール、５員〜１０員のヘテロアリール、（Ｃ３〜Ｃ１０）シクロアルキル、または３員〜１０員のヘテロシクリルに必要に応じて縮合しており；
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ_２ＯＲ’’、−ＣＨ_２ＮＲ’’_２、−Ｃ（Ｏ）Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ’’）_２から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択される。 In some embodiments, the present invention relates to Formula II :.

A compound of, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, provided in Formula II:
m is 0 to 3;
Each R ¹ independently has a halogen (eg, Cl, F), -H,-(C1-C6) alkyl, -OH, -O ((C1-C6) alkyl) (eg, -OME), -NO. _{Selected from 2} , -CN, -CF ₃ , and -OCF ₃ , where R ¹ is independently substituted with 0-5 R';
R ² is:
Selected from −H, −C (O) NR ₂ , and (C6-C10) -aryl- (eg, phenyl);
R ³ is:
-(C1-C6) alkyl,-(C2-C6) alkenyl (eg-CH = CH ₂ ), -C≡CH, -CN, halogen (eg Br), -SO ₂ ((C6-C10)- Aryl), -SO _{2 (} (C1-C6) alkyl), -C (O) N ((C1-C6) alkyl) ₂ , -C (O) NH ₂ , -C (O) O ((C1-C6) ) Alkyl), -C (O) ((C1-C6) alkyl),-(C6-C10) aryl, 5-membered to 10-membered heteroaryl (eg, 5-membered heteroaryl, eg, substituted as needed) Was done

), And 5-member to 10-membered heterocyclyls (eg, 5-membered heterocyclyls, eg, substituted as needed).

), Where R ³ is independently replaced by 0-5 R';
R ⁴ and R ⁵ are -H, halogen and-(C1-C6) alkyl, respectively;
R ⁶ is, -H and - is selected from (C1 -C6) alkyl;
Each R is independent:
H-,
(C1-C12) -aliphatic-,
(C3 to C10) -Cycloalkyl-,
(C3 to C10) -Cycloalkenyl-,
[(C3 to C10) -cycloalkyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkyl] -O- (C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl] -O- (C1 to C12) -aliphatic-,
(C6 to C10) -aryl-,
(C6 to C10) -aryl- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-O- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-N (R'')-(C1 to C12) aliphatic-,
Heterocyclyl of 3 to 10 members-,
(3-10 member heterocyclyl)-(C1-C12) Aliphatic-,
(3-10 member heterocyclyl) -O- (C1-C12) aliphatic-,
(3-10 member heterocyclyl) -N (R'')-(C1-C12) aliphatic-,
5-10 member heteroaryl-,
(5- to 10-membered heteroaryl)-(C1-C12) -aliphatic-,
(5-membered to 10-membered heteroaryl) -O- (C1-C12) -aliphatic-; and (5-membered to 10-membered heteroaryl) -N (R'')-(C1-C12) -aliphatic −
Selected from;
Here the heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO ₂ , and the heteroaryl is N, NH, O, And has 1 to 4 heteroatoms selected independently of S;
Where each existence of R is independently replaced by 0-5 R';
Alternatively, if two R groups are attached to the same atom, these two R groups, together with the atom to which they are attached, are N, NH, O, S, SO, and SO. It is possible to form a 3- to 10-membered aromatic or non-aromatic ring with 0 to 4 heteroatoms independently selected from _{2, where the ring is 0 to 5 Rs.} 'Is substituted as needed, and this ring is required for (C6-C10) aryl, 5-membered to 10-membered heteroaryl, (C3-C10) cycloalkyl, or 3-membered to 10-membered heterocyclyl. Condensed according to;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, -CH ₂ OR " _{, -CH 2} NR" ₂ , and -C (O) N (R'. ') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R') ₂ ;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-. , (C6 to C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1-C6) -alkyl-, (5-membered) It is selected from 10-membered heteroaryl) -O- (C1-C6) -alkyl- and (C6-C10) -aryl-O- (C1-C6) -alkyl-.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式ＩＩにおいて：
ｍは、０〜３であり；
各Ｒ^１は独立して、ハロゲン（例えば、Ｃｌ、Ｆ）および−Ｏ（（Ｃ１〜Ｃ６）アルキル）（例えば、−ＯＭｅ）から選択され、ここでＲ^１は独立して、０個〜５個のＲ’で置換されており；
Ｒ^２は：
−Ｈ、−Ｃ（Ｏ）ＮＲ_２、および（Ｃ６〜Ｃ１０）−アリール−（例えば、フェニル）から選択され；
Ｒ^３は：
ハロゲン（例えば、Ｂｒ）、５員〜１０員のヘテロアリール（例えば、５員のヘテロアリール、例えば、必要に応じて置換された

）、および５員〜１０員のヘテロシクリル（例えば、５員のヘテロシクリル、例えば、必要に応じて置換された

）から選択され、ここでＲ^３は独立して、０個〜５個のＲ’で置換されており；
Ｒ^４およびＲ^５は、各々−Ｈであり；
Ｒ^６は、−Ｈであり；
各Ｒは独立して：
Ｈ−、
（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ３〜Ｃ１０）−シクロアルキル−、
（Ｃ３〜Ｃ１０）−シクロアルケニル−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−、
（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
３員〜１０員のヘテロシクリル−、
（３員〜１０員のヘテロシクリル）−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
５員〜１０員のヘテロアリール−、
（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ１２）−脂肪族−、
（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−；および
（５員〜１０員のヘテロアリール）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）−脂肪族−
から選択され；
ここでこのヘテロシクリルは、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される１個〜４個のヘテロ原子を有し、そしてこのヘテロアリールは、Ｎ、ＮＨ、Ｏ、およびＳから独立して選択される１個〜４個のヘテロ原子を有し；
ここでＲの各存在は独立して、０個〜５個のＲ’で置換されているか；
あるいは２個のＲ基が同じ原子に結合している場合、これらの２個のＲ基は、これらが結合している原子と一緒になって、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される０個〜４個のヘテロ原子を有する３員〜１０員の芳香族または非芳香族の環を形成し得、ここでこの環は、０個〜５個のＲ’で必要に応じて置換されており、そしてこの環は、（Ｃ６〜Ｃ１０）アリール、５員〜１０員のヘテロアリール、（Ｃ３〜Ｃ１０）シクロアルキル、または３員〜１０員のヘテロシクリルに必要に応じて縮合しており；
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ_２ＯＲ’’、−ＣＨ_２ＮＲ’’_２、−Ｃ（Ｏ）Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ’’）_２から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択される。 In some embodiments, the present invention relates to Formula II :.

A compound of, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, provided in Formula II:
m is 0 to 3;
Each R ¹ is independently selected from halogens (eg Cl, F) and -O ((C1-C6) alkyl) (eg-OMe), where R ¹ is independently 0-5. Replaced by R';
R ² is:
Selected from −H, −C (O) NR ₂ , and (C6-C10) -aryl- (eg, phenyl);
R ³ is:
Halogen (eg Br), 5-membered to 10-membered heteroaryl (eg, 5-membered heteroaryl, eg, substituted as needed)

), And 5-member to 10-membered heterocyclyls (eg, 5-membered heterocyclyls, eg, substituted as needed).

), Where R ³ is independently replaced by 0-5 R';
R ⁴ and ^{R 5} are each -H;
R ⁶ is an -H;
Each R is independent:
H-,
(C1-C12) -aliphatic-,
(C3 to C10) -Cycloalkyl-,
(C3 to C10) -Cycloalkenyl-,
[(C3 to C10) -cycloalkyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkyl] -O- (C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl] -O- (C1 to C12) -aliphatic-,
(C6 to C10) -aryl-,
(C6 to C10) -aryl- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-O- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-N (R'')-(C1 to C12) aliphatic-,
Heterocyclyl of 3 to 10 members-,
(3-10 member heterocyclyl)-(C1-C12) Aliphatic-,
(3-10 member heterocyclyl) -O- (C1-C12) aliphatic-,
(3-10 member heterocyclyl) -N (R'')-(C1-C12) aliphatic-,
5-10 member heteroaryl-,
(5- to 10-membered heteroaryl)-(C1-C12) -aliphatic-,
(5-membered to 10-membered heteroaryl) -O- (C1-C12) -aliphatic-; and (5-membered to 10-membered heteroaryl) -N (R'')-(C1-C12) -aliphatic −
Selected from;
Here the heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO ₂ , and the heteroaryl is N, NH, O, And has 1 to 4 heteroatoms selected independently of S;
Where each existence of R is independently replaced by 0-5 R';
Alternatively, if two R groups are attached to the same atom, these two R groups, together with the atom to which they are attached, are N, NH, O, S, SO, and SO. It is possible to form a 3- to 10-membered aromatic or non-aromatic ring with 0 to 4 heteroatoms independently selected from _{2, where the ring is 0 to 5 Rs.} 'Is substituted as needed, and this ring is required for (C6-C10) aryl, 5-membered to 10-membered heteroaryl, (C3-C10) cycloalkyl, or 3-membered to 10-membered heterocyclyl. Condensed according to;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, -CH ₂ OR " _{, -CH 2} NR" ₂ , and -C (O) N (R'. ') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R') ₂ ;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-. , (C6 to C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1-C6) -alkyl-, (5-membered) It is selected from 10-membered heteroaryl) -O- (C1-C6) -alkyl- and (C6-C10) -aryl-O- (C1-C6) -alkyl-.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式ＩＩにおいて：
ｍは、０〜３であり；
各Ｒ^１は独立して、ハロゲン（例えば、Ｃｌ、Ｆ）、−Ｈ、−（Ｃ１〜Ｃ６）アルキル、−ＯＨ、−Ｏ（（Ｃ１〜Ｃ６）アルキル）（例えば、−ＯＭｅ）、−ＮＯ_２、−ＣＮ、−ＣＦ_３、および−ＯＣＦ_３から選択され、ここでＲ^１は独立して、０個〜５個のＲ’で置換されており；
Ｒ^２は：
−Ｈ、−（Ｃ１〜Ｃ６）アルキル、−ＯＨ、−Ｏ（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）Ｏ（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）ＮＲ_２、（Ｃ６〜Ｃ１０）−アリール−
（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ１２）脂肪族−、
（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（５員〜１０員のヘテロアリール）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、および
（３員〜１０員のヘテロシクリル）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−
から選択され、
ここでＲ^２は独立して、０個〜５個のＲ’で置換されており；
Ｒ^３は：
−（Ｃ２〜Ｃ６）アルケニル（例えば、−ＣＨ＝ＣＨ_２）および５員〜１０員のヘテロシクリル（例えば、５員のヘテロシクリル、例えば、必要に応じて置換された

）から選択され、ここでＲ^３は独立して、０個〜５個のＲ’で置換されており；
Ｒ^４およびＲ^５は各々独立して、−Ｈ、ハロゲンおよび−（Ｃ１〜Ｃ６）アルキルから選択され；
Ｒ^６は、−Ｈおよび−（Ｃ１〜Ｃ６）アルキルから選択され；
各Ｒは独立して：
Ｈ−、
（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ３〜Ｃ１０）−シクロアルキル−、
（Ｃ３〜Ｃ１０）−シクロアルケニル−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルキル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
［（Ｃ３〜Ｃ１０）−シクロアルケニル］−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−、
（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
３員〜１０員のヘテロシクリル−、
（３員〜１０員のヘテロシクリル）−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
５員〜１０員のヘテロアリール−、
（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ１２）−脂肪族−、
（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−；および
（５員〜１０員のヘテロアリール）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）−脂肪族−
から選択され；
ここでこのヘテロシクリルは、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される１個〜４個のヘテロ原子を有し、そしてこのヘテロアリールは、Ｎ、ＮＨ、Ｏ、およびＳから独立して選択される１個〜４個のヘテロ原子を有し；
ここでＲの各存在は独立して、０個〜５個のＲ’で置換されているか；
あるいは２個のＲ基が同じ原子に結合している場合、これらの２個のＲ基は、これらが結合している原子と一緒になって、Ｎ、ＮＨ、Ｏ、Ｓ、ＳＯ、およびＳＯ_２から独立して選択される０個〜４個のヘテロ原子を有する３員〜１０員の芳香族または非芳香族の環を形成し得、ここでこの環は、０個〜５個のＲ’で必要に応じて置換されており、そしてこの環は、（Ｃ６〜Ｃ１０）アリール、５員〜１０員のヘテロアリール、（Ｃ３〜Ｃ１０）シクロアルキル、または３員〜１０員のヘテロシクリルに必要に応じて縮合しており；
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ_２ＯＲ’’、−ＣＨ_２Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ’’）_２から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択される。 In some embodiments, the present invention relates to Formula II :.

A compound of, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, provided in Formula II:
m is 0 to 3;
Each R ¹ independently has a halogen (eg, Cl, F), -H,-(C1-C6) alkyl, -OH, -O ((C1-C6) alkyl) (eg, -OME), -NO. _{Selected from 2} , -CN, -CF ₃ , and -OCF ₃ , where R ¹ is independently substituted with 0-5 R';
R ² is:
-H,-(C1-C6) alkyl, -OH, -O ((C1-C6) alkyl), -C (O) O ((C1-C6) alkyl), -C (O) NR ₂ , (C6) ~ C10) -aryl-
(C6 to C10) -aryl- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-O- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-N (R'')-(C1 to C12) aliphatic-,
(5- to 10-membered heteroaryl)-(C1-C12) aliphatic-,
(5- to 10-membered heteroaryl) -O- (C1-C12) aliphatic-,
(5- to 10-membered heteroaryl) -N (R'')-(C1-C12) aliphatic-,
(3-10 member heterocyclyl)-(C1-C12) Aliphatic-,
(3-10 member heterocyclyl) -O- (C1-C12) aliphatic-and (3-10 member heterocyclyl) -N (R'')-(C1-C12) aliphatic-
Selected from
Here R ² is independently replaced by 0-5 R';
R ³ is:
-(C2-C6) alkenyl (eg, -CH = CH ₂ ) and 5- to 10-membered heterocyclyls (eg, 5-membered heterocyclyls, eg, substituted as needed).

), Where R ³ is independently replaced by 0-5 R';
R ⁴ and R ⁵ are independently selected from -H, halogen and-(C1-C6) alkyl;
R ⁶ is, -H and - is selected from (C1 -C6) alkyl;
Each R is independent:
H-,
(C1-C12) -aliphatic-,
(C3 to C10) -Cycloalkyl-,
(C3 to C10) -Cycloalkenyl-,
[(C3 to C10) -cycloalkyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkyl] -O- (C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl] -O- (C1 to C12) -aliphatic-,
(C6 to C10) -aryl-,
(C6 to C10) -aryl- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-O- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-N (R'')-(C1 to C12) aliphatic-,
Heterocyclyl of 3 to 10 members-,
(3-10 member heterocyclyl)-(C1-C12) Aliphatic-,
(3-10 member heterocyclyl) -O- (C1-C12) aliphatic-,
(3-10 member heterocyclyl) -N (R'')-(C1-C12) aliphatic-,
5-10 member heteroaryl-,
(5- to 10-membered heteroaryl)-(C1-C12) -aliphatic-,
(5-membered to 10-membered heteroaryl) -O- (C1-C12) -aliphatic-; and (5-membered to 10-membered heteroaryl) -N (R'')-(C1-C12) -aliphatic −
Selected from;
Here the heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO ₂ , and the heteroaryl is N, NH, O, And has 1 to 4 heteroatoms selected independently of S;
Where each existence of R is independently replaced by 0-5 R';
Alternatively, if two R groups are attached to the same atom, these two R groups, together with the atom to which they are attached, are N, NH, O, S, SO, and SO. It is possible to form a 3- to 10-membered aromatic or non-aromatic ring with 0 to 4 heteroatoms independently selected from _{2, where the ring is 0 to 5 Rs.} 'Is substituted as needed, and this ring is required for (C6-C10) aryl, 5-membered to 10-membered heteroaryl, (C3-C10) cycloalkyl, or 3-membered to 10-membered heterocyclyl. Condensed according to;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, -CH ₂ OR " _{, -CH 2} N (R") ₂ , -C (O) N. (R'') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R'') ₂ ;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-. , (C6 to C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1-C6) -alkyl-, (5-membered) It is selected from 10-membered heteroaryl) -O- (C1-C6) -alkyl- and (C6-C10) -aryl-O- (C1-C6) -alkyl-.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式ＩＩにおいて：
ｍは、０〜３であり；
各Ｒ^１は独立して、ハロゲン（例えば、Ｃｌ、Ｆ）および−Ｏ（（Ｃ１〜Ｃ６）アルキル）（例えば、−ＯＭｅ）から選択され、ここでＲ^１は独立して、０個〜５個のＲ’で置換されており；
Ｒ^２は：
−Ｈ、−（Ｃ１〜Ｃ６）アルキル、
（Ｃ６〜Ｃ１０）−アリール−（例えば、フェニル）、および
（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−
から選択され、
ここでＲ^２は独立して、０個〜５個のＲ’で置換されており；
Ｒ^３は：
−（Ｃ２〜Ｃ６）アルケニル（例えば、−ＣＨ＝ＣＨ_２）および５員〜１０員のヘテロシクリル（例えば、５員のヘテロシクリル、例えば、必要に応じて置換された

）から選択され、ここでＲ^３は独立して、０個〜５個のＲ’で置換されており；
Ｒ^４およびＲ^５は、各々−Ｈであり；
Ｒ^６は−Ｈであり；
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ_２ＯＲ’’、−ＣＨ_２Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ’’）_２から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択される。 In some embodiments, the present invention relates to Formula II :.

A compound of, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, provided in Formula II:
m is 0 to 3;
Each R ¹ is independently selected from halogens (eg Cl, F) and -O ((C1-C6) alkyl) (eg-OMe), where R ¹ is independently 0-5. Replaced by R';
R ² is:
-H,-(C1-C6) alkyl,
(C6-C10) -aryl- (eg, phenyl), and (C6-C10) -aryl- (C1-C12) aliphatic-
Selected from
Here R ² is independently replaced by 0-5 R';
R ³ is:
-(C2-C6) alkenyl (eg, -CH = CH ₂ ) and 5- to 10-membered heterocyclyls (eg, 5-membered heterocyclyls, eg, substituted as needed).

), Where R ³ is independently replaced by 0-5 R';
R ⁴ and ^{R 5} are each -H;
R ⁶ is -H;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, -CH ₂ OR " _{, -CH 2} N (R") ₂ , -C (O) N. (R'') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R'') ₂ ;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-. , (C6 to C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1-C6) -alkyl-, (5-membered) It is selected from 10-membered heteroaryl) -O- (C1-C6) -alkyl- and (C6-C10) -aryl-O- (C1-C6) -alkyl-.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式ＩＩにおいて：
ｍは、０〜３であり；
各Ｒ^１は独立して、ハロゲン、−Ｈ、−（Ｃ１〜Ｃ６）アルキル、−ＯＨ、−Ｏ（（Ｃ１〜Ｃ６）アルキル）、−ＮＯ_２、−ＣＮ、−ＣＦ_３、および−ＯＣＦ_３から選択され、ここでこのアルキルは独立して、０個〜５個のＲ’で置換されており；
Ｒ^２は：−（Ｃ１〜Ｃ６）アルキル、−ＯＨ、−Ｏ（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）Ｏ（（Ｃ１〜Ｃ６）アルキル）、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−Ｏ−、（３員〜１０員のヘテロシクリル）−（Ｃ１〜Ｃ１２）脂肪族−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ１２）−脂肪族−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ１２）−脂肪族−、および（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ１２）−脂肪族−Ｏ−から選択され、ここでこのアルキル、アリールまたはヘテロアリールは独立して、０個〜５個のＲ’で置換されており；
Ｒ^３は：−（Ｃ１〜Ｃ６）アルキル、−ＳＯ_２（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）Ｎ（（Ｃ１〜Ｃ６）アルキル）_２、および−Ｃ（Ｏ）Ｏ（（Ｃ１〜Ｃ６）アルキル）から選択され、ここでこのアルキルは独立して、０個〜５個のＲ’で置換されており；
Ｒ’は、本明細書中で定義されるとおりであり；
Ｒ^４およびＲ^５は各々独立して、−Ｈ、ハロゲンおよび−（Ｃ１〜Ｃ６）アルキルから選択され；そして
Ｒ^６は、−Ｈおよび−（Ｃ１〜Ｃ６）アルキルから選択される。 In some embodiments, the present invention relates to Formula II :.

A compound of, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, provided in Formula II:
m is 0 to 3;
Each R ¹ is independently a halogen, -H,-(C1-C6) alkyl, -OH, -O ((C1-C6) alkyl), -NO ₂ , -CN, -CF ₃ , and -OCF ₃ Selected from, where this alkyl is independently substituted with 0-5 R';
R ² is :-( C1 -C6) alkyl, -OH, -O ((C1~C6) alkyl), - C (O) O ((C1~C6) alkyl), (C6-C10) - aryl - ( C1-C12) Aliphatic-, (C6-C10) -aryl-O- (C1-C12) Aliphatic-, (C6-C10) -aryl- (C1-C12) Aliphatic-O-, (3 members- 10-membered heterocyclyl)-(C1-C12) aliphatic-, (5-membered to 10-membered heteroaryl)-(C1-C12) -aliphatic-, (5-membered to 10-membered heteroaryl) -O- ( Selected from C1-C12) -aliphatic-and (5- to 10-membered heteroaryl)-(C1-C12) -aliphatic-O-where the alkyl, aryl or heteroaryl is independent. Replaced by 0-5 R';
R ³ is:-(C1-C6) alkyl, -SO _{2 (} (C1-C6) alkyl), -C (O) N ((C1-C6) alkyl) ₂ , and -C (O) O ((C1) ~ C6) Alkyl), where this alkyl is independently substituted with 0-5 R';
R'as defined herein;
R ⁴ and R ⁵ are independently selected from -H, halogen and-(C1-C6) alkyl; and R ⁶ is selected from -H and-(C1-C6) alkyl.

In some of the embodiments of the compounds of formula II, m is 0, 1 or 2; when m is 1 or 2, at least one occurrence of ^{R 1} is halogen or -O ((C1 ~ C6) Alkyl) (eg, -F and -OMe);
R ² is :-( C1 -C6) alkyl (e.g., -Me), (C6~C10) - aryl - (Cl -C 12) aliphatic - _{(e.g., -CH 2 Ph), (C6~C10} ) - aryl -O- (C1-C12) aliphatic- (eg, -CH ₂ OPh) and (3-10 member heterocyclyl)-(C1-C12) aliphatic-(eg, -CH ₂ -pyrrolidin and -CH ₂₎ -Morpholine), where the aryl (eg, -Ph) or heterocyclyl (eg, pyrrolidine or morpholine) is independently selected from -F, -Me, and -OME. It is independently substituted with R', and this alkyl (eg, -Me) has 0 to 3 Rs selected from _{-N (Et) 2} and -N (Me) (CH _{2 Ph).} It is replaced independently with'.
R ³ is -C (O) O ((C1-C6) alkyl) (eg, -COOEt);
Both R ⁴ and R ⁵ are -H; and R ⁶ is -H.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式ＩＩにおいて：
ｍは、０〜３であり；
各Ｒ^１は独立して、ハロゲン、−Ｈ、−（Ｃ１〜Ｃ６）アルキル、−ＯＨ、−Ｏ（（Ｃ１〜Ｃ６）アルキル）、−ＮＯ_２、−ＣＮ、−ＣＦ_３、および−ＯＣＦ_３から選択され、ここでＲ^１は独立して、０個〜５個のＲ’で置換されており；
Ｒ^２は：
−（Ｃ１〜Ｃ６）アルキル、−ＯＨ、−Ｏ（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）Ｏ（（Ｃ１〜Ｃ６）アルキル）、
（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（Ｃ６〜Ｃ１０）−アリール−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ１２）脂肪族−、
（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、
（５員〜１０員のヘテロアリール）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−（Ｃ１〜Ｃ１２）脂肪族−、
（３員〜１０員のヘテロシクリル）−Ｏ−（Ｃ１〜Ｃ１２）脂肪族−、および
（３員〜１０員のヘテロシクリル）−Ｎ（Ｒ’’）−（Ｃ１〜Ｃ１２）脂肪族−
から選択され、
ここでＲ^２は独立して、０個〜５個のＲ’で置換されており；
Ｒ^３は：
−（Ｃ１〜Ｃ６）アルキル、−Ｃ≡Ｃ、−ＣＮ、ハロゲン、−ＳＯ_２（（Ｃ６〜Ｃ１０）−アリール）、−ＳＯ_２（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）Ｎ（（Ｃ１〜Ｃ６）アルキル）_２、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）Ｏ（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）（（Ｃ１〜Ｃ６）アルキル）、−（Ｃ６〜Ｃ１０）アリール、および５員〜１０員のヘテロアリールから選択され、ここでＲ^３は独立して、０個〜５個のＲ’で置換されており；
Ｒ^４およびＲ^５は各々独立して、−Ｈ、ハロゲンおよび−（Ｃ１〜Ｃ６）アルキルから選択され；
Ｒ^６は、−Ｈおよび−（Ｃ１〜Ｃ６）アルキルから選択され；そして
Ｒ’およびＲ’’は、本明細書中で定義されるとおりである。 In some embodiments, the present invention relates to Formula II :.

A compound of, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, provided in Formula II:
m is 0 to 3;
Each R ¹ is independently a halogen, -H,-(C1-C6) alkyl, -OH, -O ((C1-C6) alkyl), -NO ₂ , -CN, -CF ₃ , and -OCF ₃ Selected from, where R ¹ is independently replaced by 0-5 R';
R ² is:
-(C1-C6) alkyl, -OH, -O ((C1-C6) alkyl), -C (O) O ((C1-C6) alkyl),
(C6 to C10) -aryl- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-O- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-N (R'')-(C1 to C12) aliphatic-,
(5- to 10-membered heteroaryl)-(C1-C12) aliphatic-,
(5- to 10-membered heteroaryl) -O- (C1-C12) aliphatic-,
(5- to 10-membered heteroaryl) -N (R'')-(C1-C12) aliphatic-,
(3-10 member heterocyclyl)-(C1-C12) Aliphatic-,
(3-10 member heterocyclyl) -O- (C1-C12) aliphatic-and (3-10 member heterocyclyl) -N (R'')-(C1-C12) aliphatic-
Selected from
Here R ² is independently replaced by 0-5 R';
R ³ is:
-(C1-C6) alkyl, -C≡C, -CN, halogen, -SO ₂ ((C6-C10) -aryl), -SO _{2 (} (C1-C6) alkyl), -C (O) N ( (C1-C6) Alkyl) ₂ , -C (O) NH ₂ , -C (O) O ((C1-C6) Alkyl), -C (O) ((C1-C6) Alkyl),-(C6- C10) is aryl, and 5- to 10-membered heteroaryl, wherein R ³ is independently is substituted with 0 to five R ';
R ⁴ and R ⁵ are independently selected from -H, halogen and-(C1-C6) alkyl;
R ⁶ is -H and - (C1 -C6) selected from alkyl; and R 'and R''are as defined herein.

であり、
ここでＲ^３は独立して、０個〜３個のＲ’で置換されており、そしてＲ^９は、−Ｈ、−Ｍｅ、−Ｅｔ、−ＣＦ_３、イソプロピル、−ＯＭｅ、−ｔｅｒｔ−ブチル、およびシクロプロピルから選択され；
Ｒ^４とＲ^５との両方が−Ｈであり；
Ｒ^６は−Ｈであり；そして
Ｒ’は、本明細書中で定義されるとおりである。 In some embodiments of compounds of formula II:
m is 0, 1 or 2;
When m is 1 or 2, ^{the presence of at least one of R 1} is a halogen or —O ((C1-C6) alkyl);
R ² is:
-(C1-C6) alkyl, (C6-C10) -aryl- (C1-C12) aliphatic-, (C6-C10) aryl-O- (C1-C12) aliphatic-, (5-10 members) heteroaryl) - (Cl -C 12) aliphatic -, and (3-membered to 10-membered heterocyclyl) - (Cl -C 12) aliphatic - is selected from, wherein ^{R 2} is 0-3 R ' Is replaced independently with;
R ³ is halogen, -CN, -C≡C, -C (O) NH ₂ ,-(C1 to C6) alkyl, -C (O) ((C1 to C6) alkyl), -C (O) O. ((C1-C6) alkyl), -SO ₂ (Ph (Me)),

And
Here R ³ is independently substituted with 0 to 3 R', and R ⁹ is -H, -Me, -Et, -CF ₃ , isopropyl, -OME, -tert-butyl. , And cyclopropyl;
Both R ⁴ and ^{R 5} be -H;
R ⁶ is −H; and R'is as defined herein.

であり、ここでＲ^９は、−Ｈ、−Ｍｅ、−Ｅｔ、−ＣＦ_３、イソプロピル、−ＯＭｅ、および−ｔｅｒｔ−ブチルから選択される。 In some embodiments of compounds of Formula II, R ³ is:

Where R ⁹ is selected from -H, -Me, -Et, -CF ₃ , isopropyl, -OMe, and -tert-butyl.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式ＩＩＩにおいて：
ｍは、０、１、または２であり、そしてｍが１または２である場合、Ｒ^１の少なくとも１つの存在は、−Ｏ（（Ｃ１〜Ｃ６）アルキル）（例えば、−ＯＭｅ）であり；
Ｒ^２は：−（Ｃ１〜Ｃ６）アルキル（例えば、−Ｍｅ）および（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−（例えば、−ＣＨ_２Ｐｈ）から選択され；
Ｒ^３は、−Ｃ（Ｏ）Ｏ（（Ｃ１〜Ｃ６）アルキル）（例えば、−ＣＯＯＥｔ）であり；
Ｒ^４とＲ^５との両方が−Ｈであり；そして
Ｒ^６は−Ｈである。 In some embodiments, the present invention relates to Formula III :.

A compound of, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, provided in Formula III:
If m is 0, 1, or 2, and m is 1 or 2, then ^{at least one presence of R 1} is -O ((C1-C6) alkyl) (eg, -OMe);
R ² is :-( C1 -C6) alkyl (e.g., -Me) and (C6-C10) - aryl - (Cl -C 12) aliphatic - (e.g., selected from _-CH 2 Ph);
R ³ is -C (O) O ((C1-C6) alkyl) (eg, -COOEt);
Both R ⁴ and R ⁵ are -H; and R ⁶ is -H.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式ＩＶにおいて：
ｍは、０〜３であり（例えば、ｍは１であり）；
各Ｒ^１は独立して、−Ｃｌ、−Ｆ、−ＯＭｅ、および−Ｃ≡ＣＨから選択され；
Ｒ^２は、−（ＣＨ_２）_ｎＯＲ^８または−（ＣＨ_２）_ｎＯ（ＣＨ_２）_ｎＲ^８であり、ここでＲ^８の各存在は独立して、−（Ｃ１〜Ｃ６）アルキルまたは（Ｃ６〜Ｃ１０）−アリール（例えば、フェニル）であり、そしてＲ^２は独立して、０個〜５個のＲ’で置換されており；
Ｒ^３は：−ＣＮ、−Ｃ≡ＣＨ、−Ｃ≡Ｃ−（Ｃ１〜Ｃ６）アルキル、−Ｃ≡Ｃ−フェニル、

から選択され、ここでＲ^３は、０個〜５個のＲ’で置換されており；
Ｒ^４およびＲ^５の各存在は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
各Ｒ^６は独立して、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ_２ＯＲ’’、−ＣＨ_２ＮＲ’’_２、−Ｃ（Ｏ）Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ’’）_２から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、−（Ｃ１〜Ｃ６）−脂肪族、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択され、ここでＲ’’の各存在は：ハロゲン、−Ｒ^ｏ、−ＯＲ^ｏ、オキソ、−ＣＨ_２ＯＲ^ｏ、−ＣＨ_２Ｎ（Ｒ^ｏ）_２、−Ｃ（Ｏ）Ｎ（Ｒ^ｏ）_２、−Ｃ（Ｏ）ＯＲ^ｏ、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ^ｏ）_２から選択される０個〜５個の置換基で独立して置換されており、ここでＲ^ｏの各存在は独立して：
−（Ｃ１〜Ｃ６）−脂肪族、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、および（Ｃ６〜Ｃ１０）−アリール−から選択される。
上記実施形態のうちのいくつかにおいて、Ｒ^３は：

から選択され、
ここでＲ’’の各存在は独立して、−（Ｃ１〜Ｃ６）−アルキル（例えば、直鎖または分枝状）、−Ｃ≡ＣＨ、フェニル、チオフェン、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−から選択され、ここで各Ｒ’’は、ハロゲン、−Ｒ^ｏ、−ＯＲ^ｏ、オキソ、−ＣＨ_２ＯＲ^ｏ、−ＣＨ_２Ｎ（Ｒ^ｏ）_２、−Ｃ（Ｏ）Ｎ（Ｒ^ｏ）_２、−Ｃ（Ｏ）ＯＲ^ｏ、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ^ｏ）_２から選択される０個〜３個の置換基で独立して置換されており、ここでＲ^ｏの各存在は独立して、−（Ｃ１〜Ｃ６）−脂肪族、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、および（Ｃ６〜Ｃ１０）−アリール−から選択される。 In another aspect, the invention is based on Formula IV :.

Compounds, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof are provided in Formula IV:
m is 0 to 3 (for example, m is 1);
Each R ¹ is independently selected from -Cl, -F, -OMe, and -C≡CH;
R ² is − (CH ₂ ) _n OR ⁸ or − (CH ₂ ) _n O (CH ₂ ) _n R ⁸ where each presence of R ⁸ is independently − (C1 to C6) alkyl or (C6-C10) - aryl (e.g., phenyl), and and ^{R 2} are independently, is substituted with 0 to five R ';
R ³ is: -CN, -C≡CH, -C≡C- (C1-C6) alkyl, -C≡C-phenyl,

Selected from, where R ³ is replaced by 0-5 R';
Each presence of R ⁴ and R ⁵ is independently -H or- (C1-C6) alkyl;
Each ^{R 6} is independently, -H or - be (C1 -C6) alkyl;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, -CH ₂ OR " _{, -CH 2} NR" ₂ , and -C (O) N (R'. ') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R') ₂ ;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl,-(C1-C6) -aryl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl. 5, 10-membered heteroaryl-, (C6-C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1) ~ C6) -alkyl-, (5-member to 10-membered heteroaryl) -O- (C1-C6) -alkyl-, and (C6-C10) -aryl-O- (C1-C6) -alkyl- And here each presence of R'' is: halogen, -R ^o , -OR ^o , oxo, -CH ₂ OR ^o , -CH ₂ N (R ^o ) ₂ , -C (O) N (R ^o ). _{^{2, -C (O) oR o}} , -NO 2, -NCS, -CN, -CF 3, independently with 0 to 5 substituents selected from -OCF _3, and -N ^(R _{o) 2} And where each existence of ^{Ro is independent:}
-(C1-C6) -aliphatic, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-, and (C6-C10) -aryl-selected from ..
In some of the above embodiments, R ³ is:

Selected from
Here, each presence of R'' is independent of-(C1-C6) -alkyl (eg, linear or branched), -C≡CH, phenyl, thiophene, (5- to 10-membered heteroaryl). )-(C1-C6) -alkyl-, and (C6-C10) -aryl- (C1-C6) -alkyl-where each R'' is halogen, -R ^o , -OR ^o,. Oxo, -CH ₂ OR ^o , -CH ₂ N (R ^o ) ₂ , -C (O) N (R ^o ) ₂ , -C (O) OR ^o , -NO ₂ , -NCS, -CN, -CF _3, -OCF _3, and -N ^(R _o) are independently substituted with 0-3 substituents selected from _2, wherein each occurrence of ^{R o} is independently, - (C1 to It is selected from C6) -aliphatic, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-, and (C6-C10) -aryl-.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式ＩＶにおいて：
ｍは、０〜３であり；
各Ｒ^１は独立して、ハロゲン（例えば、Ｃｌ）、−Ｈ、−（Ｃ１〜Ｃ６）アルキル、−Ｃ≡ＣＨ、−ＯＨ、−Ｏ（（Ｃ１〜Ｃ６）アルキル）（例えば、ＯＭｅ）、−ＮＯ_２、−ＣＮ、−ＣＦ_３、および−ＯＣＦ_３から選択され、ここでＲ^１は独立して、０個〜５個のＲ’で置換されており；
Ｒ^２は、−ＯＲ^８、−ＳＲ^８、−（ＣＨ_２）_ｎＯＲ^８（例えば、−ＣＨ_２ＯＭｅ、−ＣＨ_２ＯＥｔ、−ＣＨ_２Ｏイソプロピル、−ＣＨ_２Ｏピリジル）、−（ＣＨ_２）_ｎＯ（ＣＨ_２）_ｎＲ^８、−（ＣＨ_２）_ｐＲ^８および−（ＣＨ_２）_ｎＮ（Ｒ’’）Ｒ^１０から選択され、ここでｎは、０〜４から選択される整数であり；ｐは、２〜４から選択される整数であり；各Ｒ^８は独立して、−（Ｃ１〜Ｃ６）アルキル、−（Ｃ３〜Ｃ１０）−シクロアルキル、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ^８の各存在は独立して、０個〜５個のＲ’で置換されており；各Ｒ^１０は独立して、−（Ｃ３〜Ｃ１０）−シクロアルキル、３員〜１０員のヘテロシクリル−、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ^１０の各存在は独立して、０個〜５個のＲ’で置換されており；ここでＲ^２は独立して、０個〜５個のＲ’で置換されており；
Ｒ^３は：
−Ｈ、−ＣＮ、ハロゲン（例えば、Ｂｒ）、−（Ｃ１〜Ｃ６）アルキル、−Ｃ≡ＣＨ、−ＳＯ_２（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）Ｎ（（Ｃ１〜Ｃ６）アルキル）_２、）、−Ｃ（Ｏ）ＮＨ（（Ｃ１〜Ｃ６）脂肪族）_２（例えば、−Ｃ（Ｏ）ＮＨ（（Ｃ２〜Ｃ６）アルキニル）_２）、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、−Ｃ（Ｏ）（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）Ｏ（（Ｃ１〜Ｃ６）アルキル）、５員または６員のヘテロシクリル−（例えば、必要に応じて置換された

または必要に応じて置換された

）、および５員または６員のヘテロアリール（例えば、必要に応じて置換された

、必要に応じて置換された

から選択され、ここでＲ^９は、−Ｍｅ、−Ｅｔ、イソプロピル、−ＣＦ_３、−ＯＭｅ、−ＯＥｔ、−Ｏ−イソプロピル、−ＣＨ_２ＮＭｅ_２、およびシクロプロピルから選択され；ここでＲ^３は独立して、０個〜５個のＲ’で置換されており；
Ｒ^４およびＲ^５は各々独立して、−Ｈ、ハロゲンおよび−（Ｃ１〜Ｃ６）アルキルから選択され；
Ｒ^６は、−Ｈおよび−（Ｃ１〜Ｃ６）アルキルから選択され；
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ_２ＯＲ’’、−ＣＨ_２Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ’’）_２から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択される。 In another aspect, the invention is based on Formula IV :.

Compounds, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof are provided in Formula IV:
m is 0 to 3;
Each R ¹ is independently a halogen (eg Cl), −H, − (C1-C6) alkyl, −C≡CH, −OH, −O ((C1-C6) alkyl) (eg, OME), Selected from −NO ₂ , −CN, −CF ₃ , and −OCF ₃ , where R ¹ is independently substituted with 0-5 R';
R ² is -OR ⁸ , -SR ⁸ ,-(CH ₂ ) _n OR ⁸ (eg, -CH ₂ OMe, -CH ₂ OEt, -CH ₂ Oisopropyl, -CH ₂ O pyridyl),-(CH _2). ) _N O (CH ₂ ) _n R ⁸ ,-(CH ₂ ) _p R ⁸ and-(CH ₂ ) _n N (R'') R ¹⁰ where n is selected from 0 to 4. It is an integer; p is an integer selected from 2 to 4; each R ⁸ is independently − (C1 to C6) alkyl,-(C3 to C10) -cycloalkyl, (C6 to C10)-. aryl, or a 5- to 10-membered heteroaryl, wherein each occurrence of R ⁸ is independently is substituted with 0 to five R '; each R ¹⁰ is independently - ( C3 -C10) - cycloalkyl, 3-membered to 10-membered heterocyclyl -, (C6-C10) - aryl, or a 5- to 10-membered heteroaryl, wherein each occurrence of ^{R 10} is independently 0 Replaced by 5 to 5 R'; where R ² is independently replaced by 0 to 5 R';
R ³ is:
-H, -CN, halogen (eg Br),-(C1-C6) alkyl, -C≡CH, -SO _{2 (} (C1-C6) alkyl), -C (O) N ((C1-C6)) Alkyl) ₂ ,), -C (O) NH ((C1-C6) aliphatic) ₂ (for example, -C (O) NH ((C2-C6) alkynyl) ₂ ), (C6-C10) -aryl- (C1-C12) Aliphatic-, -C (O) ((C1-C6) Alkyne), -C (O) O ((C1-C6) Alkyne), 5-membered or 6-membered heterocyclyl-(eg, required Was replaced according to

Or replaced as needed

), And 5- or 6-membered heteroaryl (eg, substituted as needed)

, Replaced as needed

Selected from, where R ⁹ is selected from -Me, -Et, isopropyl, -CF ₃ , -OME, -OEt, -O-isopropyl, -CH ₂ NMe ₂ , and cyclopropyl; where R ^{3 is selected.} Are independently replaced by 0-5 R';
R ⁴ and R ⁵ are independently selected from -H, halogen and-(C1-C6) alkyl;
R ⁶ is, -H and - is selected from (C1 -C6) alkyl;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, -CH ₂ OR " _{, -CH 2} N (R") ₂ , -C (O) N. (R'') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R'') ₂ ;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-. , (C6 to C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1-C6) -alkyl-, (5-membered) It is selected from 10-membered heteroaryl) -O- (C1-C6) -alkyl- and (C6-C10) -aryl-O- (C1-C6) -alkyl-.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式ＩＶにおいて：
ｍは１であり；
Ｒ^１は、Ｒ’で必要に応じて置換された−Ｃ≡ＣＨであり；
Ｒ^２は、−ＯＲ^８、−ＳＲ^８、−（ＣＨ_２）_ｎＯＲ^８（例えば、−ＣＨ_２ＯＭｅ、−ＣＨ_２ＯＥｔ、−ＣＨ_２Ｏイソプロピル、−ＣＨ_２Ｏピリジル）、−（ＣＨ_２）_ｎＯ（ＣＨ_２）_ｎＲ^８、−（ＣＨ_２）_ｐＲ^８および−（ＣＨ_２）_ｎＮ（Ｒ’’）Ｒ^１０から選択され、ここでｎは、０〜４から選択される整数であり；ｐは、２〜４から選択される整数であり；各Ｒ^８は独立して、−（Ｃ１〜Ｃ６）アルキル、−（Ｃ３〜Ｃ１０）−シクロアルキル、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ^８の各存在は独立して、０個〜５個のＲ’で置換されており；各Ｒ^１０は独立して、−（Ｃ３〜Ｃ１０）−シクロアルキル、３員〜１０員のヘテロシクリル−、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ^１０の各存在は独立して、０個〜５個のＲ’で置換されており；ここでＲ^２は独立して、０個〜５個のＲ’で置換されており；
Ｒ^３は：
−Ｈ、−ＣＮ、ハロゲン（例えば、Ｂｒ）、−（Ｃ１〜Ｃ６）アルキル、−Ｃ≡ＣＨ、−ＳＯ_２（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）Ｎ（（Ｃ１〜Ｃ６）アルキル）_２、）、−Ｃ（Ｏ）ＮＨ（（Ｃ１〜Ｃ６）脂肪族）_２（例えば、−Ｃ（Ｏ）ＮＨ（（Ｃ１〜Ｃ６）アルキニル）_２）、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、−Ｃ（Ｏ）（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）Ｏ（（Ｃ１〜Ｃ６）アルキル）、５員または６員のヘテロシクリル−（例えば、必要に応じて置換された

または必要に応じて置換された

）、および５員または６員のヘテロアリール（例えば、必要に応じて置換された

、必要に応じて置換された

から選択され、ここでＲ^９は、−Ｍｅ、−Ｅｔ、イソプロピル、−ＣＦ_３、−ＯＭｅ、−ＯＥｔ、−Ｏ−イソプロピル、−ＣＨ_２ＮＭｅ_２、およびシクロプロピルから選択され；ここでＲ^３は独立して、０個〜５個のＲ’で置換されており；
Ｒ^４およびＲ^５は各々独立して、−Ｈ、ハロゲンおよび−（Ｃ１〜Ｃ６）アルキルから選択され；
Ｒ^６は、−Ｈおよび−（Ｃ１〜Ｃ６）アルキルから選択され；
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ_２ＯＲ’’、−ＣＨ_２ＮＲ’’_２、−Ｃ（Ｏ）Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ’’）_２から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択される。 In another aspect, the invention is based on Formula IV :.

Compounds, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof are provided in Formula IV:
m is 1;
R ¹ is -C≡CH, optionally substituted with R';
R ² is -OR ⁸ , -SR ⁸ ,-(CH ₂ ) _n OR ⁸ (eg, -CH ₂ OMe, -CH ₂ OEt, -CH ₂ Oisopropyl, -CH ₂ O pyridyl),-(CH _2). ) _N O (CH ₂ ) _n R ⁸ ,-(CH ₂ ) _p R ⁸ and-(CH ₂ ) _n N (R'') R ¹⁰ where n is selected from 0 to 4. It is an integer; p is an integer selected from 2 to 4; each R ⁸ is independently − (C1 to C6) alkyl,-(C3 to C10) -cycloalkyl, (C6 to C10)-. aryl, or a 5- to 10-membered heteroaryl, wherein each occurrence of R ⁸ is independently is substituted with 0 to five R '; each R ¹⁰ is independently - ( C3 -C10) - cycloalkyl, 3-membered to 10-membered heterocyclyl -, (C6-C10) - aryl, or a 5- to 10-membered heteroaryl, wherein each occurrence of ^{R 10} is independently 0 Replaced by 5 to 5 R'; where R ² is independently replaced by 0 to 5 R';
R ³ is:
-H, -CN, halogen (eg Br),-(C1-C6) alkyl, -C≡CH, -SO _{2 (} (C1-C6) alkyl), -C (O) N ((C1-C6)) Alkyl) ₂ ,), -C (O) NH ((C1-C6) aliphatic) ₂ (for example, -C (O) NH ((C1-C6) alkynyl) ₂ ), (C6-C10) -aryl- (C1-C12) Aliphatic-, -C (O) ((C1-C6) Alkyne), -C (O) O ((C1-C6) Alkyne), 5-membered or 6-membered heterocyclyl-(eg, required Was replaced according to

Or replaced as needed

), And 5- or 6-membered heteroaryl (eg, substituted as needed)

, Replaced as needed

Selected from, where R ⁹ is selected from -Me, -Et, isopropyl, -CF ₃ , -OME, -OEt, -O-isopropyl, -CH ₂ NMe ₂ , and cyclopropyl; where R ^{3 is selected.} Are independently replaced by 0-5 R';
R ⁴ and R ⁵ are independently selected from -H, halogen and-(C1-C6) alkyl;
R ⁶ is, -H and - is selected from (C1 -C6) alkyl;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, -CH ₂ OR " _{, -CH 2} NR" ₂ , and -C (O) N (R'. ') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R') ₂ ;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-. , (C6 to C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1-C6) -alkyl-, (5-membered) It is selected from 10-membered heteroaryl) -O- (C1-C6) -alkyl- and (C6-C10) -aryl-O- (C1-C6) -alkyl-.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式ＩＶにおいて：
ｍは１であり；
各Ｒ^１は、Ｒ’で必要に応じて置換された−Ｃ≡ＣＨであり；
Ｒ^２は、−（ＣＨ_２）_ｎＯＲ^８（例えば、−ＣＨ_２ＯＭｅ、−ＣＨ_２ＯＥｔ、−ＣＨ_２Ｏイソプロピル、−ＣＨ_２Ｏピリジル）であり；ここでＲ^２は独立して、０個〜５個のＲ’で置換されており；
Ｒ^３は：
５員または６員のヘテロシクリル−（例えば、必要に応じて置換された

または必要に応じて置換された

）、および５員または６員のヘテロアリール（例えば、必要に応じて置換された

、または必要に応じて置換された

）から選択され；ここでＲ^３は独立して、０個〜５個のＲ’で置換されており；
Ｒ^４およびＲ^５は、各々−Ｈであり；
Ｒ^６は−Ｈであり；そして
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ_２ＯＲ’’、−ＣＨ_２ＮＲ’’_２、−Ｃ（Ｏ）Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ’’）_２から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択される。 In another aspect, the invention is based on Formula IV :.

Compounds, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof are provided in Formula IV:
m is 1;
Each R ¹ is -C≡CH, optionally substituted with R';
R ² is-(CH ₂ ) _n OR ⁸ (eg, -CH ₂ OMe, -CH ₂ OEt, -CH ₂ Oisopropyl, -CH ₂ O pyridyl); where R ² is independently 0. Replaced by 5 to 5 R';
R ³ is:
5- or 6-membered heterocyclyl-(eg, substituted as needed)

Or replaced as needed

), And 5- or 6-membered heteroaryl (eg, substituted as needed)

, Or replaced as needed

); Where R ³ is independently replaced by 0-5 R';
R ⁴ and ^{R 5} are each -H;
R ⁶ is -H; and where each presence of R'is independent, halogen, -R ", -OR", oxo, -CH ₂ OR " _{, -CH 2} NR" ₂ , Select from -C (O) N (R'') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R'') _2. Beed;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-. , (C6 to C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1-C6) -alkyl-, (5-membered) It is selected from 10-membered heteroaryl) -O- (C1-C6) -alkyl- and (C6-C10) -aryl-O- (C1-C6) -alkyl-.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式ＩＶにおいて：
ｍは、０〜３であり；
ｍが１または２である場合、Ｒ^１の少なくとも１個の存在は、−ハロゲンまたは−Ｏ（（Ｃ１〜Ｃ６）アルキル）であり；
各Ｒ^１は独立して、ハロゲン（例えば、Ｃｌ）、−Ｈ、−（Ｃ１〜Ｃ６）アルキル、−Ｃ≡ＣＨ、−ＯＨ、−Ｏ（（Ｃ１〜Ｃ６）アルキル）（例えば、ＯＭｅ）、−ＮＯ_２、−ＣＮ、−ＣＦ_３、および−ＯＣＦ_３から選択され、ここでＲ^１は独立して、０個〜５個のＲ’で置換されており；
Ｒ^２は、−ＯＲ^８、−ＳＲ^８、−（ＣＨ_２）_ｎＯＲ^８（例えば、−ＣＨ_２ＯＭｅ、−ＣＨ_２ＯＥｔ、−ＣＨ_２Ｏイソプロピル、−ＣＨ_２Ｏピリジル）、−（ＣＨ_２）_ｎＯ（ＣＨ_２）_ｎＲ^８、−（ＣＨ_２）_ｐＲ^８および−（ＣＨ_２）_ｎＮ（Ｒ’’）Ｒ^１０から選択され、ここでｎは、０〜４から選択される整数であり；ｐは、２〜４から選択される整数であり；各Ｒ^８は独立して、−（Ｃ１〜Ｃ６）アルキル、−（Ｃ３〜Ｃ１０）−シクロアルキル、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ^８の各存在は独立して、０個〜５個のＲ’で置換されており；各Ｒ^１０は独立して、−（Ｃ３〜Ｃ１０）−シクロアルキル、３員〜１０員のヘテロシクリル−、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ^１０の各存在は独立して、０個〜５個のＲ’で置換されており；ここでＲ^２は独立して、０個〜５個のＲ’で置換されており；
Ｒ^３は：
−Ｃ≡ＣＨ、−Ｃ（Ｏ）ＮＨ（（Ｃ１〜Ｃ６）脂肪族）_２（例えば、−Ｃ（Ｏ）ＮＨ（（Ｃ１〜Ｃ６）アルキニル）_２）、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、５員または６員のヘテロシクリル−（例えば、必要に応じて置換された

または必要に応じて置換された

）、必要に応じて置換された

、および必要に応じて置換された

から選択され；ここでＲ^３は独立して、０個〜５個のＲ’で置換されており；
Ｒ^４およびＲ^５は各々独立して、−Ｈ、ハロゲンおよび−（Ｃ１〜Ｃ６）アルキルから選択され；
Ｒ^６は、−Ｈおよび−（Ｃ１〜Ｃ６）アルキルから選択され；そして
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ_２ＯＲ’’、−ＣＨ_２ＮＲ’’_２、−Ｃ（Ｏ）Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ’’）_２から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択される。 In another aspect, the invention is based on Formula IV :.

Compounds, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof are provided in Formula IV:
m is 0 to 3;
When m is 1 or 2, ^{the presence of at least one of R 1} is -halogen or -O ((C1-C6) alkyl);
Each R ¹ is independently a halogen (eg Cl), −H, − (C1-C6) alkyl, −C≡CH, −OH, −O ((C1-C6) alkyl) (eg, OME), Selected from −NO ₂ , −CN, −CF ₃ , and −OCF ₃ , where R ¹ is independently substituted with 0-5 R';
R ² is -OR ⁸ , -SR ⁸ ,-(CH ₂ ) _n OR ⁸ (eg, -CH ₂ OMe, -CH ₂ OEt, -CH ₂ Oisopropyl, -CH ₂ O pyridyl),-(CH _2). ) _N O (CH ₂ ) _n R ⁸ ,-(CH ₂ ) _p R ⁸ and-(CH ₂ ) _n N (R'') R ¹⁰ where n is selected from 0 to 4. It is an integer; p is an integer selected from 2 to 4; each R ⁸ is independently − (C1 to C6) alkyl,-(C3 to C10) -cycloalkyl, (C6 to C10)-. aryl, or a 5- to 10-membered heteroaryl, wherein each occurrence of R ⁸ is independently is substituted with 0 to five R '; each R ¹⁰ is independently - ( C3 -C10) - cycloalkyl, 3-membered to 10-membered heterocyclyl -, (C6-C10) - aryl, or a 5- to 10-membered heteroaryl, wherein each occurrence of ^{R 10} is independently 0 Replaced by 5 to 5 R'; where R ² is independently replaced by 0 to 5 R';
R ³ is:
-C≡CH, -C (O) NH ((C1-C6) aliphatic) ₂ (for example, -C (O) NH ((C1-C6) alkynyl) ₂ ), (C6-C10) -aryl-( C1-C12) Aliphatic-5- or 6-membered heterocyclyl-(eg, substituted as needed)

Or replaced as needed

), Replaced as needed

, And replaced as needed

Selected from; where R ³ is independently replaced by 0-5 R';
R ⁴ and R ⁵ are independently selected from -H, halogen and-(C1-C6) alkyl;
R ⁶ is selected from -H and- (C1-C6) alkyl; and where each presence of R'is independent, halogen, -R ", -OR", oxo, -CH ₂ OR'. ', -CH ₂ NR'' ₂ , -C (O) N (R'') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R'') ₂ selected from;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-. , (C6 to C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1-C6) -alkyl-, (5-membered) It is selected from 10-membered heteroaryl) -O- (C1-C6) -alkyl- and (C6-C10) -aryl-O- (C1-C6) -alkyl-.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式ＩＶにおいて：
ｍは、０〜３であり；
各Ｒ^１は独立して、ハロゲン（例えば、Ｃｌ）、−Ｃ≡ＣＨ、および−Ｏ（（Ｃ１〜Ｃ６）アルキル）（例えば、ＯＭｅ）から選択され、ここでＲ^１は独立して、０個〜５個のＲ’で置換されており；
Ｒ^２は、−（ＣＨ_２）_ｎＯＲ^８（例えば、−ＣＨ_２ＯＭｅ、−ＣＨ_２ＯＥｔ、−ＣＨ_２Ｏ−イソプロピル、−ＣＨ_２Ｏ−ピリジル）であり、ここでｎは、０〜４から選択される整数であり；Ｒ^８は、−（Ｃ１〜Ｃ６）アルキル、−（Ｃ３〜Ｃ１０）−シクロアルキル、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ^８の各存在は独立して、０個〜５個のＲ’で置換されており；ここでＲ^２は独立して、０個〜５個のＲ’で置換されており；
Ｒ^３は：
−Ｃ≡ＣＨ、−Ｃ（Ｏ）ＮＨ（（Ｃ１〜Ｃ６）脂肪族）_２（例えば、−Ｃ（Ｏ）ＮＨ（（Ｃ１〜Ｃ６）アルキニル）_２））、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ１２）脂肪族−、５員または６員のヘテロシクリル−（例えば、必要に応じて置換された

または必要に応じて置換された

）、必要に応じて置換された

、および必要に応じて置換された

から選択され；ここでＲ^３は独立して、０個〜５個のＲ’で置換されており；
Ｒ^４およびＲ^５は、各々が−Ｈであり；
Ｒ^６は、−Ｈまたは−（Ｃ１〜Ｃ６）アルキルであり；そして
ここでＲ’の各存在は独立して、ハロゲン、−Ｒ’’、−ＯＲ’’、オキソ、−ＣＨ_２ＯＲ’’、−ＣＨ_２ＮＲ’’_２、−Ｃ（Ｏ）Ｎ（Ｒ’’）_２、−Ｃ（Ｏ）ＯＲ’’、−ＮＯ_２、−ＮＣＳ、−ＣＮ、−ＣＦ_３、−ＯＣＦ_３および−Ｎ（Ｒ’’）_２から選択され；
ここでＲ’’の各存在は独立して、Ｈ、−（Ｃ１〜Ｃ６）−アルキル、（Ｃ３〜Ｃ６）−シクロアルキル、３員〜６員のヘテロシクリル、５員〜１０員のヘテロアリール−、（Ｃ６〜Ｃ１０）−アリール−、（５員〜１０員のヘテロアリール）−（Ｃ１〜Ｃ６）−アルキル−、（Ｃ６〜Ｃ１０）−アリール−（Ｃ１〜Ｃ６）−アルキル−、（５員〜１０員のヘテロアリール）−Ｏ−（Ｃ１〜Ｃ６）−アルキル−、および（Ｃ６〜Ｃ１０）−アリール−Ｏ−（Ｃ１〜Ｃ６）−アルキル−から選択される。 In another aspect, the invention is based on Formula IV :.

Compounds, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof are provided in Formula IV:
m is 0 to 3;
Each R ¹ is independently selected from halogens (eg Cl), -C≡CH, and -O ((C1-C6) alkyl) (eg OMe), where R ¹ is independently 0. Replaced by 5 to 5 R';
R ² is − (CH ₂ ) _n OR ⁸ (eg, −CH ₂ OME, −CH ₂ OEt, −CH ₂ O-isopropyl, −CH ₂ O − pyridyl), where n is 0-4. An integer selected from; R ⁸ is a-(C1-C6) alkyl,-(C3-C10) -cycloalkyl, (C6-C10) -aryl, or 5- to 10-membered heteroaryl. wherein each occurrence of R ⁸ is independently 'is substituted by; wherein R ² is independently 0 to five R' 0 to five R is substituted with;
R ³ is:
-C≡CH, -C (O) NH ((C1-C6) aliphatic) ₂ (for example, -C (O) NH ((C1-C6) alkynyl) ₂ )), (C6-C10) -aryl- (C1-C12) Aliphatic-5- or 6-membered heterocyclyl-(eg, substituted as needed)

Or replaced as needed

), Replaced as needed

, And replaced as needed

Selected from; where R ³ is independently replaced by 0-5 R';
R ⁴ and ^{R 5} each be -H;
R ⁶ is -H or- (C1-C6) alkyl; and where each presence of R'is independent, halogen, -R'', -OR'', oxo, -CH ₂ OR''. , -CH ₂ NR'' ₂ , -C (O) N (R'') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF _{3 and-} Selected from N (R'') _2;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-. , (C6 to C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1-C6) -alkyl-, (5-membered) It is selected from 10-membered heteroaryl) -O- (C1-C6) -alkyl- and (C6-C10) -aryl-O- (C1-C6) -alkyl-.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式ＩＶにおいて：
ｍは、０、１、または２であり、そしてｍが１または２である場合、Ｒ^１の少なくとも１つの存在は、−Ｏ（（Ｃ１〜Ｃ６）アルキル）（例えば、−ＯＭｅ）であり；
Ｒ^２はＯＲ^８であり、ここでＲ^８は、０個〜３個のハロゲン（例えば−Ｆ）で置換された（Ｃ６〜Ｃ１０）−アリール（例えば、フェニル）であり；
Ｒ^３は、−Ｃ（Ｏ）Ｏ（（Ｃ１〜Ｃ６）アルキル）（例えば、−ＣＯＯＥｔ）であり；
Ｒ^４とＲ^５との両方が−Ｈであり；そして
Ｒ^６は−Ｈである。 In another aspect, the invention is based on Formula IV :.

Compounds, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof are provided in Formula IV:
If m is 0, 1, or 2, and m is 1 or 2, then ^{at least one presence of R 1} is -O ((C1-C6) alkyl) (eg, -OMe);
R ² is OR ⁸ , where R ⁸ is (C6-C10) -aryl (eg, phenyl) substituted with 0 to 3 halogens (eg, -F);
R ³ is -C (O) O ((C1-C6) alkyl) (eg, -COOEt);
Both R ⁴ and R ⁵ are -H; and R ⁶ is -H.

の化合物、またはその薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体、もしくは組み合わせを提供し、式ＩＶにおいて：
ｍは、０〜３であり；
ｍが１または２である場合、Ｒ^１の少なくとも１個の存在は、−ハロゲンまたは−Ｏ（（Ｃ１〜Ｃ６）アルキル）であり；
各Ｒ^１は独立して、ハロゲン、−Ｈ、−（Ｃ１〜Ｃ６）アルキル、−ＯＨ、−Ｏ（（Ｃ１〜Ｃ６）アルキル）、−ＮＯ_２、−ＣＮ、−ＣＦ_３、および−ＯＣＦ_３から選択され、ここでＲ^１は独立して、０個〜５個のＲ’で置換されており；
Ｒ^２は、−ＯＲ^８、−ＳＲ^８、−（ＣＨ_２）_ｎＯＲ^８、−（ＣＨ_２）_ｎＯ（ＣＨ_２）_ｎＲ^８、−（ＣＨ_２）_ｐＲ^８および−（ＣＨ_２）_ｎＮ（Ｒ’’）Ｒ^１０から選択され、ここでｎは、０〜４から選択される整数であり；ｐは、２〜４から選択される整数であり；各Ｒ^８は独立して、−（Ｃ１〜Ｃ６）アルキル、−（Ｃ３〜Ｃ１０）−シクロアルキル、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ^８の各存在は独立して、０個〜５個のＲ’で置換されており；各Ｒ^１０は独立して、−（Ｃ３〜Ｃ１０）−シクロアルキル、３員〜１０員のヘテロシクリル−、（Ｃ６〜Ｃ１０）−アリール、または５員〜１０員のヘテロアリールであり、ここでＲ^１０の各存在は独立して、０個〜５個のＲ’で置換されており；ここでＲ^２は独立して、０個〜５個のＲ’で置換されており；
Ｒ^３は：
−Ｈ、−ＣＮ、ハロゲン、−（Ｃ１〜Ｃ６）アルキル、−ＳＯ_２（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）Ｎ（（Ｃ１〜Ｃ６）アルキル）_２、−Ｃ（Ｏ）（（Ｃ１〜Ｃ６）アルキル）、−Ｃ（Ｏ）Ｏ（（Ｃ１〜Ｃ６）アルキル）、

から選択され、ここでＲ^９は、−Ｍｅ、−Ｅｔ、イソプロピル、−ＣＦ_３、−ＯＭｅ、−ＯＥｔ、−Ｏ−イソプロピル、−ＣＨ_２ＮＭｅ_２、およびシクロプロピルから選択され；ここでＲ^３は独立して、０個〜５個のＲ’で置換されており；
Ｒ^４およびＲ^５は各々独立して、−Ｈ、ハロゲンおよび−（Ｃ１〜Ｃ６）アルキルから選択され；
Ｒ^６は、−Ｈおよび−（Ｃ１〜Ｃ６）アルキルから選択され；そして
Ｒ’およびＲ’’は、本明細書中で定義されるとおりである。 In another aspect, the invention is based on Formula IV :.

Compounds, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof are provided in Formula IV:
m is 0 to 3;
When m is 1 or 2, ^{the presence of at least one of R 1} is -halogen or -O ((C1-C6) alkyl);
Each R ¹ is independently a halogen, -H,-(C1-C6) alkyl, -OH, -O ((C1-C6) alkyl), -NO ₂ , -CN, -CF ₃ , and -OCF ₃ Selected from, where R ¹ is independently replaced by 0-5 R';
R ² is −OR ⁸ , −SR ⁸ , − (CH ₂ ) _n OR ⁸ , − (CH ₂ ) _n O (CH ₂ ) _n R ⁸ , − (CH ₂ ) _p R ⁸ and − (CH ₂ ). _n N (R'') R ¹⁰ selected, where n is an integer selected from 0 to 4; p is an integer selected from 2 to 4; each R ⁸ is independent. , - (C1 -C6) alkyl, - (C3 -C10) - cycloalkyl, (C6-C10) - aryl or 5-membered to 10-membered heteroaryl, wherein each occurrence of ^{R 8} is independently , 0 is substituted with to five R '; each ^{R 10} is independently, - (C3 -C10) - cycloalkyl, 3-membered to 10-membered heterocyclyl -, (C6-C10) - aryl, Or a 5- to 10-membered heteroaryl, where ^{each presence of R 10} is independently substituted with 0-5 R'; where R ² is independent, 0- Replaced by 5 R';
R ³ is:
-H, -CN, Halogen,-(C1-C6) Alkyl, -SO _{2 (} (C1-C6) Alkyl), -C (O) N ((C1-C6) Alkyl) ₂ , -C (O) ( (C1-C6) alkyl), -C (O) O ((C1-C6) alkyl),

Selected from, where R ⁹ is selected from -Me, -Et, isopropyl, -CF ₃ , -OME, -OEt, -O-isopropyl, -CH ₂ NMe ₂ , and cyclopropyl; where R ^{3 is selected.} Are independently replaced by 0-5 R';
R ⁴ and R ⁵ are independently selected from -H, halogen and-(C1-C6) alkyl;
R ⁶ is -H and - (C1 -C6) selected from alkyl; and R 'and R''are as defined herein.

であり、ここでこのアルキルは、０個〜３個のＲ’で独立して置換されており；Ｒ^９は、−Ｍｅ、−Ｅｔ、イソプロピル、および−ＣＦ_３から選択され；
Ｒ^４とＲ^５との両方が−Ｈであり；
Ｒ^６は−Ｈであり；そして
Ｒ’は、本明細書中で定義されるとおりである。 In some embodiments of the compound of formula IV:
m is 0, 1, or 2;
R ² is −OR ⁸ , − (CH ₂ ) _n OR ⁸ , − (CH ₂ ) _n O (CH ₂ ) _n R ⁸ , where n is 1, and R ⁸ is − (C1). ~ C6) Alkyl, (C6-C10) -aryl or 5- to 10-membered heteroaryl, where R ⁸ is independently substituted with 0 to 3 R';
R ³ is a halogen, −H, −CN, − (C1 to C6) alkyl, −C (O) ((C1 to C6) alkyl), −C (O) O ((C1 to C6) alkyl),

Where the alkyl is independently substituted with 0 to 3 R'; R ⁹ is selected from -Me, -Et, isopropyl, and -CF _3;
Both R ⁴ and ^{R 5} be -H;
R ⁶ is −H; and R'is as defined herein.

およびこれらの薬学的に受容可能な塩、水和物、溶媒和物、多形、異性体または組み合わせが挙げられる。 Examples of specific compounds of the present application are:

And these pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or combinations thereof.

である。上記の例の各々に対して、化合物は、本明細書中に記載される基の特定の値を有し得る。 The invention also includes various combinations ^{of R 1} , R ² and R ³ as described above. These combinations can then be combined with any or all of the values of the other variables described herein. For example, R ¹ can be -OR or halogen ;; R ² is (C1-C4) ^{-alkyl-, -OR 8} ,-(CH ₂ ) _n OR ⁸ or-(CH _{2 ) n} O (CH). ₂ ) _n R ⁸ ; optionally R ³ can be -C (O) OR or -C (O) N (R) ₂ . In another example, R ¹ is -OR or halogen; R ² is (C1-C4) ^{-alkyl-, -OR 8} ,-(CH ₂ ) _n OR ⁸ or-(CH ₂ ) _n O ( CH ₂ ) _n R ⁸ ; R ³ is a 5- or 6-membered heteroaryl, eg,

Is. For each of the above examples, the compound may have specific values of the groups described herein.

Unless otherwise indicated, any of the embodiments described herein are intended to correspond to compounds in unlabeled as well as isotope-labeled forms. Isotopically labeled compounds are according to the formulas given herein, except that one or more atoms are replaced by atoms with a selected atomic mass or mass number. Has a structure to be drawn. Examples of isotopes that can be incorporated into the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine isotopes, such as ² H, ³ H, ¹¹ C, ¹³ C, respectively. ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, ¹²⁵ I can be mentioned. The present invention, various isotopically labeled compounds as defined herein, including, for example, ^{3 H,} 13 those into which radioactive isotopes such as ^C and ^{14 C} are present. Such isotopically labeled compounds are metabolic studies (preferably, ^{14 C),} reaction kinetic studies (e.g., ^{2 H,} or ^{3 H),} detection techniques or imaging techniques, for example, positron emission tomography ( It is useful in PET) or single photon emission computed tomography (SPECT) (including a tissue distribution assay of a drug or substrate) or radiological treatment of a patient. In ^{particular, 18} F or labeled compound may be particularly preferred for PET or SPECT studies. Isotopically labeled compounds of the invention and their prodrugs are usually made by using readily available isotope-labeled reagents in place of the isotope-unlabeled reagents. It can be prepared by performing the procedures disclosed in the schemes or examples and preparation methods described below.

Any individual embodiment listed herein may individually define or combine formulas I, II, III or IV to result in a preferred embodiment of the invention.

スキーム２．Ｘ、Ｙ、Ｚ、ＶおよびＷがピラゾール環を形成する式ＩまたはＩＩＩの化合物の一般的な合成。

スキーム３．Ｘ、Ｙ、Ｚ、ＶおよびＷがフェノキシ置換１，２，３−トリアゾール環を形成する式Ｉの化合物、または式ＩＩの化合物の一般的な合成。

スキーム４．Ｘ、Ｙ、Ｚ、ＶおよびＷによって形成されるトリアゾロ環上での多岐にわたる官能化を可能にする式ＩまたはＩＩの化合物の一般的な合成。

スキーム５．Ｘ、Ｙ、Ｚ、ＶおよびＷが、アミノメチル置換１，２，３−トリアゾール環を形成する式Ｉの化合物、または式ＩＩの化合物一般的な合成。

スキーム６．Ｘ、Ｙ、Ｚ、ＶおよびＷが、アラルキル置換もしくはヘテロアラルキル置換１，２，３−トリアゾール環を形成する式Ｉの化合物、または式ＩＩの化合物の一般的な合成。

スキーム７．Ｘ、Ｙ、Ｚ、ＶおよびＷが、置換１，２，４−トリアゾール環を形成する式ＩまたはＩＶの化合物の一般的な合成。

スキーム８．Ｘ、Ｙ、Ｚ、ＶおよびＷが、メチル置換１，２，３−トリアゾール環を形成する式Ｉの化合物、または式ＩＩの化合物の一般的な合成。

スキーム９．Ｘ、Ｙ、Ｚ、ＶおよびＷが、ベンジル置換１，２，３−トリアゾール環を形成する式Ｉの化合物、または式ＩＩの化合物の一般的な合成。

スキーム１０．Ｘ、Ｙ、Ｚ、ＶおよびＷが、置換トリアゾール環（例えば、１，２，３−トリアゾール環または１，２，４−トリアゾール環）を形成し、上部のイミダゾールが、１０（ａ）および１０（ｂ）に図示されるような１，２，４−オキサジアゾール（ｏｘａｄｉｚａｏｌｅ）環で置換されている、式Ｉ、ＩＩまたはＩＶの化合物の一般的な合成。

スキーム１０ａ．Ｒ^３が必要に応じて置換されたジヒドロオキサゾールまたはオキサジニル環である化合物の一般的な合成が、スキーム１０ａに図示されている。

スキーム１０ｂ（ａ）および１０ｂ（ｂ）．Ｒ^３が必要に応じて置換されたオキサゾールまたはイソオキサゾールである化合物の一般的な合成が、スキーム１０ｂ（ａ）および１０ｂ（ｂ）に図示されている。

スキーム１０ｃ．Ｒ^３が必要に応じて置換されたアルキニル基である化合物の一般的な合成が、スキーム１０ｃに図示されている。

General Synthetic Methods The compounds of the present invention can usually be prepared by methods known to those of skill in the art. Schemes 1-10 below provide general synthetic routes for preparing compounds of formulas I-IV. Various parts of the molecule as illustrated by the general schemes below may be synthesized by substituting other equivalent schemes that will be readily apparent to those skilled in the art of organic chemistry. ..
Scheme 1. General synthesis of compounds of formula I, or compounds of formula II, in which X, Y, Z, V and W form a 1,2,3-triazole ring.

Scheme 2. General synthesis of compounds of formula I or III in which X, Y, Z, V and W form a pyrazole ring.

Scheme 3. General synthesis of compounds of formula I, or compounds of formula II, in which X, Y, Z, V and W form a phenoxy-substituted 1,2,3-triazole ring.

Scheme 4. General synthesis of compounds of formula I or II that allow a wide range of functionalizations on the triazolo ring formed by X, Y, Z, V and W.

Scheme 5. A general synthesis of a compound of formula I, or a compound of formula II, in which X, Y, Z, V and W form an aminomethyl-substituted 1,2,3-triazole ring.

Scheme 6. A general synthesis of a compound of formula I, or a compound of formula II, in which X, Y, Z, V and W form an aralkyl or heteroaralkyl substituted 1,2,3-triazole ring.

Scheme 7. General synthesis of compounds of formula I or IV in which X, Y, Z, V and W form a substituted 1,2,4-triazole ring.

Scheme 8. General synthesis of compounds of formula I, or compounds of formula II, in which X, Y, Z, V and W form a methyl-substituted 1,2,3-triazole ring.

Scheme 9. General synthesis of compounds of formula I, or compounds of formula II, in which X, Y, Z, V and W form a benzyl-substituted 1,2,3-triazole ring.

Scheme 10. X, Y, Z, V and W form a substituted triazole ring (eg, 1,2,3-triazole ring or 1,2,4-triazole ring) and the upper imidazole is 10 (a) and 10 General synthesis of a compound of formula I, II or IV substituted with a 1,2,4-oxadiazole ring as illustrated in (b).

Scheme 10a. General synthesis of R ³ is dihydrooxazole or oxazinyl ring is optionally substituted compounds is illustrated in Scheme 10a.

Schemes 10b (a) and 10b (b). The general synthesis of compounds in which R ³ is optionally substituted oxazole or isoxazole is illustrated in Schemes 10b (a) and 10b (b).

Scheme 10c. The general synthesis of a compound in which R ³ is an alkynyl group substituted as needed is illustrated in Scheme 10c.

As will be appreciated by those of skill in the art, compounds of formulas I-IV with variables other than those shown above can be prepared by modifying chemical reagents or synthetic routes.

Pharmaceutical Compositions and Modes of Administration The present invention relates to pharmaceutically acceptable carriers and compounds of formulas I-IV or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or combinations thereof. To provide a pharmaceutical composition comprising.

The basic nitrogen-containing groups present in the compounds of the present invention are lower alkyl halides (eg, methyl chloride, ethyl chloride, propyl chloride and butyl chloride, methyl bromide, ethyl bromide, propyl bromide and butyl bromide, and Methyl iodide, ethyl iodide, propyl iodide and butyl iodide); dialkyl sulphate (eg dimethyl sulphate, diethyl sulphate, dibutyl sulphate and diamyl sulphate), long-chain halides (eg decyl chloride, lauryl chloride, myristyl chloride). And stearyl chloride, decyl bromide, lauryl bromide, myristyl bromide and stearyl bromide, as well as decyl iodide, lauryl iodide, myristyl iodide and stearyl iodide), aralkyl halides (eg, benzyl bromide and stearyl bromide). It can be quaternized with agents such as phenethyl). This gives a water-soluble or oil-soluble or water-dispersible or oil-dispersible product.

It will be recognized that the compounds and agents used in the compositions of the invention should preferably easily penetrate the blood-brain barrier when administered peripherally. However, compounds that cannot penetrate the blood-brain barrier can still be effectively administered directly to the central nervous system, eg, by intraventricular or other neurocompatible pathways.

In some embodiments of the present invention, .alpha.5-containing GABA A _R positive allosteric modulators are formulated with a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers that can be used in these compositions include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffers such as phosphates, glycine, and the like. Sorbic acid, potassium sorbate, a partial glyceride mixture of vegetable saturated fatty acids with water and salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicic acid, tri. Examples include, but are not limited to, magnesium silicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol and wool fat. In other embodiments, carriers are not used. For example, .alpha.5-containing GABA _A R agonists (e.g., .alpha.5-containing GABA _A receptor positive allosteric modulators) as a component of alone or pharmaceutical formulation (therapeutic composition), may be administered. .alpha.5-containing GABA A _R agonists (e.g., .alpha.5-containing GABA _A receptor positive allosteric modulators) may be formulated for administration in any convenient way for use in medicine for humans.

In some embodiments, the therapeutic method of the invention comprises the step of locally (topically), systemically or locally (locally) administering a composition of a compound or agonist. For example, therapeutic compositions of the compounds or agents of the invention can be, for example, injected (eg, intravenously, subcutaneously or intramuscularly), inhaled or ventilated (either through the mouth or nose) or orally, cheeks. It can be formulated for administration by lateral, sublingual, transdermal, nasal or parenteral administration. The compositions of the compounds or agents described herein can be formulated as part of an implantable tablet or device, or for sustained release or sustained release. When administered parenterally, the therapeutic composition of a compound or agent for use in the present invention is preferably a pyrogen-free, physiologically acceptable form. Techniques and formulations are generally described in Remington's Pharmaceutical Sciences, Meade Publishing Co., Ltd. , Easton, PA.

In certain embodiments, pharmaceutical compositions suitable for parenteral administration, the α5 containing GABA A _R positive allosteric modulators, antioxidants, buffers, bacteriostats, the blood of the intended recipient of the formulation Solutes or suspensions or thickeners that make it isotonic with one or more pharmaceutically acceptable sterilized isotonic aqueous or non-aqueous solutions, dispersions, suspensions or It can be included with an emulsion, or with a sterilized powder that can be reconstituted into a sterilized injectable solution or dispersion immediately prior to use. Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (eg, glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, olive oil, etc. Vegetable oils, as well as injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by using a coating material such as lecithin, in the case of dispersions by maintaining the required particle size, and by using surfactants.

compositions containing α5 containing GABA A _R positive allosteric modulators, adjuvants (e.g., preserving, wetting agents, emulsifying agents and dispersing agents) may also include. The inclusion of various antibacterial and antifungal agents, such as parabens, chlorobutanols, phenols, sorbic acid, etc., can ensure the prevention of microbial action. It may also be desirable to include isotonic agents (sugar, sodium chloride, etc.) in the composition. In addition, long-term absorption of injectable pharmaceutical forms can occur by including absorption-delaying agents such as aluminum monostearate and gelatin.

In certain embodiments of the present invention, compositions comprising the α5 containing GABA A _R positive allosteric modulators are, for example, those capsules, cachets, pills, tablets, lozenges (main component is flavored, Usually using syrup and acacia or tragant), in the form of powders, pills, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or lozenges (inert base such as gelatin and glycerin or sucrose and used acacia) as such (in each of which, .alpha.5-containing GABA a _R positive allosteric modulator of a predetermined amount As an active ingredient), can be administered orally.

Solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, and granules), the one or composition beyond that comprising the α5 containing GABA A _R positive allosteric modulators are one or Can be mixed with more than pharmaceutically acceptable carriers (eg, sodium citrate or dicalcium phosphate) and / or any of the following: (1) Fillers or bulking agents (eg, starch, lactose, sucrose). , Glucose, mannitol and / or silicic acid); (2) binding agents (eg, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or acacia); (3) wetting agents (eg, glycerol); (4). Disintegrants (eg, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate); (5) Dissolution retarders (eg, paraffin); (6) Absorption enhancers (eg, quaternary). Ammonium compounds); (7) Wetting agents (eg, cetyl alcohol and glycerol monostearate); (8) Absorbents (eg, kaolin and bentonite clay); (9) Lubricants (eg, talc, calcium stearate, stearic acid) Magnesium, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof); and (10) colorants. In the case of capsules, tablets and pills, the pharmaceutical composition may also include a buffer. Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or lactose, as well as high molecular weight polyethylene glycol.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms, in addition to the α5 containing GABA A _R positive allosteric modulators, inert diluents commonly used in the art (e.g., water or other solvents), solubilizing agents and emulsifiers such as ethyl alcohol ( Ethanol), isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (especially cottonseed oil, lacquer oil, corn oil, germ oil, olive oil, castor oil and sesame oil). ), glycerol, tetrahydrofuryl alcohols, polyethylene glycol and sorbitan fatty acid esters and mixtures thereof. Oral compositions may include adjuvants (eg, wetting agents, emulsifying and suspending agents, sweeteners, flavors, colorants, flavors and preservatives) as well as inert diluents.

In addition to the active compounds, the suspensions include suspending agents (eg, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters), microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragant and them. May contain a mixture of.

As described herein, compounds, agents and compositions thereof may be administered for sustained release, controlled release or sustained release. The term "sustained release" is widely recognized in the field of pharmacy and over a long period of time (eg, over an hour or equal to an hour) (over a long period of time or throughout an hour) to an environment. As used herein, it refers to the controlled release of an active compound or agent from a dosage form. The sustained release dosage form can release the drug at a substantially constant rate over a long period of time, or a substantially constant amount of the drug can be released in an increasing manner over a long period of time. As used herein, the term "sustained release" is used in pharmacy as the terms "controlled release", "long-term release", "sustained release", "delayed release" or "sustained release" are used. Includes these terms. In some embodiments, the sustained release formulation is administered in the form of a patch or pump.

Those skilled in the art, such as a physician, the amount of α5 containing GABA A _R positive allosteric modulators that are required to treat the subject using the compositions and methods of the present invention can readily be determined. Dosing regimen, for example, various factors which modify the action of the α5 containing GABA A _R positive allosteric modulators, the severity or stage of the disease, the route of administration, as well as features specific to the individual, such as age, weight, size and cognitive disorders It is understood that it can be determined for the individual, taking into account the degree of.

It is well known in the art that normalization to body surface area is an appropriate method for extrapolating doses between species. To calculate the human equivalent dose (HED) from the dose used in treating age-dependent cognitive impairment in rats, the formula HED (mg / kg) = dose in rats (mg / kg) x 0. 16 can be used (see Estimating the Safe Starting Dose in Clinical Trials for Therapy Volunters, December 2002, CenterRe-Bio For example, using that formula, a dose of 10 mg / kg in rats is equivalent to 1.6 mg / kg in humans. This conversion is based on the more general formula HED = animal dose in mg / kg x (body weight of animals in kg / human body weight in kg) ^0.33 .

In certain embodiments of the present invention, the dose of α5 containing GABA _A R positive allosteric modulators is 0.0001 to 100 / kg / day (which, given a typical human subject of 70 kg, 0 .007-7000 mg / day).

In certain embodiments of the invention, the dosing interval is once every 12 or 24 hours. It may be administered at lower frequency intervals, eg, once every 6 hours.

Implants, when administered by the device or sustained release formulations or sustained release formulations, .alpha.5-containing GABA A _R positive allosteric modulators, once, or optionally, periodically once throughout the life of the patient or it Can be administered more times. Other dosing intervals between these dosing intervals for clinical application may also be used, which may be determined by one of ordinary skill in the art according to the methods of the invention.

The desired dosing time can be determined by one of ordinary skill in the art by performing routine experiments. For example, .alpha.5-containing GABA _A R positive allosteric modulators, 1-4 weeks, 1-3 months, over 3-6 months, 6-12 months, 1-2 years or a period exceeding it, until the life of the patient Can be administered.

The compositions of the present invention, in addition to the α5 containing GABA A _R positive allosteric modulators, may also contain other therapeutically useful agents. These other therapeutically useful agents, according to the method of the present invention, in a single formulation may be administered simultaneously or sequentially with the α5 containing GABA A _R positive allosteric modulators.

The compositions described herein can be adapted and modified to be suitable for the application undertaken, and the compositions described herein have other suitable uses. It will be understood by those skilled in the art that it can be used in. For example, the compositions of the present application may further comprise a second therapeutic agent. Such other additions and modifications do not deviate from the scope of the invention.

Pharmaceutical Compositions Containing Antipsychotics The compounds or compositions of the present application are associated with said schizophrenia or bipolar disorder in a subject having or at risk of schizophrenia or bipolar disorder (eg, mania). Can be used in combination with antipsychotics in treating cognitive impairment. Antipsychotics or pharmaceutically acceptable salts, hydrates, solvates or polymorphs thereof useful in the methods and compositions of the invention include both typical and atypical antipsychotics. Is done. In some embodiments, the compounds or compositions of the invention can be used to treat one or more positive and / or negative symptoms and cognitive impairment associated with schizophrenia. In some embodiments, the compounds or compositions of the invention can be used to treat one or more symptoms as well as cognitive impairment associated with bipolar disorder (particularly mania). In some embodiments of the invention, the compounds or compositions of the invention prevent or delay the progression of schizophrenia or bipolar disorder (particularly mania) cognitive impairment in said subjects.

In some embodiments, suitable antipsychotics for use in the present invention are selected from atypical antipsychotics. Examples of such atypical antipsychotics include US Pat. Nos. 4,734,416; 5,006,528; 4,145,434; 5,763,476; No. 3,539,573; No. 5,229,382; No. 5,532,372; No. 4,879,288; No. 4,804,663; No. 4,710 , 500; 4,831,031; and 5,312,925; and those disclosed in European Patents EP402644 and EP368388, as well as their pharmaceutically acceptable salts, hydration. Substances, solvates and polymorphs include, but are not limited to.

In some embodiments, atypical antipsychotics suitable for use in the present invention include aripiprazole, asenapine, clozapine, iroperidone, olanzapine, lulacidone, paliperidone, quetiapine, risperidone and ziprasidone, and their pharmaceutically. Acceptable salts, hydrates, solvates and polymorphs include, but are not limited to. In some embodiments, the antipsychotic agents suitable for use herein are aripiprazole (Bristol-Myers Squibb), olanzapine (Lily) and ziprasidone (Pfizer), and their pharmaceutically acceptable salts. It is selected from hydrates, solvates and polymorphs.

In some embodiments, suitable antipsychotic agents for use in the present invention are acepromazine, bemperidol, bromazepam, bromperidol, chlorpromazine, chlorprothixene, crothiapine, siamemazine, diazepam, dixylazine, droperidol, flupenti. Xol, flufenazine, fluspirylene, haloperidol, heptaminol, isopropamide iodide, levomepromazine, levoslupyrido, loxapine, merperone, mesolidazine, morindone, oxypertine, oxyprotepine, oxyprothepine, penfluridor, perazine, perizin , Pipamperone, Pipothiadin, Prochlorperazine, Promazine, Promethazine, Protipendyl, Pyridoxin, Sulpyrido, Slutprid, Tetravenazine, Thioproperazine, Thioridazine, Thiaprid, Thiothixene, Trifloperazine, Triflupromazine, Trihexifenidil and Zuclopenti Typical antipsychotics including, but not limited to, xol, and their pharmaceutically acceptable salts, hydrates, solvates and polymorphs.

In some embodiments of the invention, the antipsychotic agent or a pharmaceutically acceptable salt, hydrate, solvate or polymorphic thereof is a dopamine agonist (eg, a dopamine D1 receptor antagonist or agonist, dopamine D. ₂ Receptor Agonist or Partial Agonist, Dopamine D3 Receptor Antagonist or Partial Agonist, Dopamine D4 Receptor Agonist), Glutamic Agonist, N-Methyl-D-Aspartic Acid (NMDA) Receptor Positive Allosteric Modulator, Glycin Reuptake Inhibitor, Glutamic Acid Reuptake inhibitor, metabolically regulated glutamate receptor (mGluR) agonist or positive allosteric modulator (PAM) (eg, mGluR2 / 3 agonist or PAM), glutamate receptor glur5 positive allosteric modulator (PAM), M1 muscarinic acetylcholine receptor (mAChR) Positive allosteric modulator (PAM), histamine H3 receptor antagonist, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) / quinic acid receptor agonist, ampakines (CX-516), glutathione Prodrugs, noradrenaline agonists (eg, alpha-2 adrenaline agonists or antagonists and catechol-O-methyltransferase (COMT) inhibitors), serotonin receptor modulators (eg, 5-HT _2A receptor antagonists, 5-HT _1A receptor moieties) Agonists, 5-HT _2C agonists and 5-HT6 antagonists, serotonin 2C agonists, choline agonists (eg, alpha-7 nicotine receptor agonists or PAMs, alpha 4-beta2 nicotine receptor agonists, nicotine receptor allosteric modulators and acetyls) Cholinesterase inhibitors, muscarinic receptor agonists and antagonists), cannabinoid CB1 antagonists, neurokinin 3 antagonists, neurotensin agonists, monoamine oxidase (MAO) B inhibitors, PDE10 inhibitors, neural nitrogen monoxide synthase (nNOS) inhibitors, Neural steroids and neurotrophic factors Can be selected from a combination.

In some embodiments, α5-containing GABA _A receptor positive allosteric modulators as described herein and antipsychotic agents as described herein, or pharmaceutically acceptable salts thereof. The hydrates, solvates or polymorphs are administered simultaneously or sequentially, or in separate formulations packaged in a single formulation or together. In other embodiments, α5-containing GABA _A receptor positive allosteric modulators and antipsychotics, or pharmaceutically acceptable salts, hydrates, solvates or polymorphs thereof, are administered via different routes. .. As used herein, "combination" includes administration by either of these formulations or routes of administration.

Pharmaceutical Compositions Containing Memantin The compounds or compositions of the present application are subjects requiring or at risk of cognitive impairment associated with central nervous system (CNS) disorders (age-related cognitive impairment, mild cognitive impairment). Cognitive impairment (MCI), amnestic MCI, age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), precursor AD, post-traumatic stress disorder (PTSD), schizophrenia Central nervous system (CNS) in (including, but not limited to, subjects having or at risk of cognitive impairment associated with dementia or bipolar disorder, muscular atrophic lateral sclerosis (ALS) and cancer treatment). It can be used in combination with memantin or its derivatives or analogs in treating cognitive impairment associated with the disorder.

Memantine, also chemically known as 3,5-dimethyladamantane-1-amine or 3,5-dimethyltricyclo [3.3.1.1 ^3,7 ] decane-1-amine, has a moderate affinity. It is a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist with sex. Trademark names for memantine include Axura® and Akatinol® (Merz), Namenda® (Forest Laboratories), Ebiza® and Abixa® (Lundbeck) and Memax®. Trademark) (Unipharm). Memantine is currently available in the United States and more than 42 countries around the world. Memantine has been approved in the United States for the treatment of moderate to severe Alzheimer's disease (AD) at doses of up to 28 mg / day. Memantine and some of its derivatives and analogs useful in the present invention are described in US Pat. No. 3,391,142; 4,122,193; 4,273,774; and 5,061. , 703, all of which are incorporated herein by reference. Other Memantin derivatives or Memantin analogs useful in the present invention include US Patent Application Publications US2004087658, US20050113458, US200060205822, US2009081259, US20090124659 and US20100227852; European Patent Application Publication EP2260839A2; European Patent EP1682109B1; Is incorporated herein by reference), including, but not limited to, the compounds disclosed in this specification. As used in the present invention, memantine includes memantine and its derivatives and analogs, as well as hydrates, polymorphs, prodrugs, salts and solvates thereof. As used herein, memantine also includes compositions containing memantine or its derivatives or analogs or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof. Here, the composition further comprises, as needed, at least one additional therapeutic agent (eg, a therapeutic agent useful for treating CNS disorders or cognitive disorders associated therewith). In some embodiments, the memantine composition suitable for use in the present invention comprises a second therapeutic agent, memantine and donepezil (trade name Alicept).

In other embodiments of the invention, α5-containing GABA _A receptor positive allosteric modulators and memantine (or memantine derivatives / analogs) or pharmaceutically acceptable salts, hydrates, solvates, polyforms or prodrugs thereof. Are administered simultaneously or sequentially, or in separate formulations packaged in a single formulation or together. In other embodiments, α5-containing GABA _A receptor positive allosteric modulators and memantine (or memantine derivatives / analogs) or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof are different. Administered via the route. As used herein, "combination" includes administration by either of these formulations or routes of administration.

Pharmaceutical Compositions Containing Acetylcholinesterase Inhibitors (AChE-I) The compounds or compositions of the present application are subjects in need or risk of cognitive impairment associated with central nervous system (CNS) disorders. (Age-related cognitive impairment, mild cognitive impairment (MCI), forgetfulness MCI, age-related memory disorder (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), precursor AD, post-traumatic Includes, but is not limited to, stress disorder (PTSD), schizophrenia or bipolar disorder, muscle atrophic lateral sclerosis (ALS) and subjects with or at risk of cognitive impairment associated with cancer treatment. ) Can be used in combination with an acetylcholinesterase inhibitor in treating cognitive impairment associated with central nervous system (CNS) impairment.

AChE-I known to those of skill in the art are (i) reversible non-competitive or reversible competitive inhibitors, (ii) irreversible inhibitors, and / or (iii) quasi-irreversible inhibition. It may belong to the subcategory of agents.

In certain embodiments, AChE-I useful in the present invention include PCT applications WO2014403992 and WO2002032412; European Patent No. 468187; 481429-A; and US Pat. No. 4,816,456; 4,895,841; 5,041,455; 5,106,856; 5,602,176; 6,677,330; 7,340,299 No. 7,635,709; No. 8,058,268; No. 8,741,808; and No. 8,853,219 (all of which are herein by reference). Incorporated).

Representative AChE-Is that can be used in accordance with the present invention in certain embodiments include ungelemine, radstigmine, demepotassium, Phospholine, edrophonium, cognex, plaridoxime ( 2-PAM), Pyridostigmine (Mestinon), Physostigmine (Serin, Antillium), Abmenonium (Myterase), Galantamine (Reminyl, Razadyne), Ribastigmine (Exelon, SZDineZ) Prostigmin, Vagostigmin), Alicept (Donepezil, E2020), Lactucopicrin, monoamineaclydin and their derivatives, piperidin and piperazin derivatives, N-benzyl-piperidin derivatives, piperidinyl-alkanoyl heterocyclic compounds, 4- (1-benzyl: piperidil). Examples include, but are not limited to, substituted condensed quinoline derivatives and cyclic amide derivatives. Other representative AChE-Is include carbamate and organophosphonate compounds, such as Metrifonate (Trichlorphon). Benzazepinols, such as galantamine, are also useful AChE-I. In some embodiments, AChE-I suitable for use in combination with the compounds and compositions of the present application includes Donepezil (Aricept), Galantamine (Razadyne) or Rivastigmine (Excellon).

In other embodiments of the invention, the α5-containing GABA _A receptor positive allosteric modulator and AChE-I or pharmaceutically acceptable salts, hydrates, solvates, polyforms or prodrugs thereof are simultaneous or continuous. Administered either as a single formulation or as a separate formulation packaged together. In other embodiments, α5-containing GABA _A receptor positive allosteric modulators and AChE-I or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof are administered via different routes. Will be done. As used herein, "combination" includes administration by either of these formulations or routes of administration.

In some embodiments, the compounds and compositions described herein are for use as pharmaceuticals. In some embodiments, the compounds and compositions of the invention are for use in treating said cognitive deficits in subjects who require or are at risk of cognitive deficits associated with CNS disorders. belongs to. In some embodiments, cognitive impairment associated with CNS impairment includes, but is not limited to, age-related cognitive impairment, mild cognitive impairment (MCI), forgetfulness MCI (aMCI), age-related memory impairment (AAMI), Age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), precursor AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, muscular atrophic lateral sclerosis (ALS), cancer Treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, let syndrome, compulsive behavior and substance addiction.

In some embodiments, the present application relates herein in the preparation of a pharmaceutical for the treatment of said cognitive impairment in a subject in need of or at risk of treating a cognitive disorder associated with a CNS disorder. Provided for use of the compounds or compositions described in. In some embodiments, cognitive impairment associated with CNS impairment includes, but is not limited to, age-related cognitive impairment, mild cognitive impairment (MCI), forgetfulness MCI (aMCI), age-related memory impairment (AAMI), Age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), precursor AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, muscular atrophic lateral sclerosis (ALS), cancer Treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, let syndrome, compulsive behavior and substance addiction.

Methods for Assessing Cognitive Disorders Animal models serve as an important tool for developing and assessing treatments for cognitive impairment associated with CNS disorders. The characteristics that characterize cognitive impairment in animal models usually extend to cognitive impairment in humans. Therefore, efficacy in such animal models is expected to predict efficacy in humans. The degree of cognitive impairment in an animal model for CNS impairment and the effectiveness of treatment methods for said CNS impairment can be tested and confirmed using various cognitive tests.

The radial maze (RAM) behavioral task is specifically an example of a cognitive test that examines spatial memory (Chappel et al., Neuropharmacology 37: 481-487, 1998). The RAM device consists of, for example, eight runways (arms) arranged equidistantly. The maze track protrudes from each side of the central platform. A food depression is located at the distal end of each runway. Food is used as a reward. Blocks can be placed to prevent entry into any track. It may also provide a number of additional maze clues around the device. After the acclimatization and training periods, the subject's spatial memory can be tested in RAM under conditions treated with the control compound or test compound. As part of that test, subjects are pre-treated with vehicle control or one of the test compounds in a series of doses prior to the trial. At the beginning of each trial, the direction of a subset of the 8-way maze is blocked. Subjects can get food on an unblocked track that is allowed access during this first "information phase" of the trial. The subject is then subjected to a period of delay, eg, 60, between the information period and the subsequent "memorization test" that allows access to all eight tracks because the barriers on the labyrinth have been removed. It is taken out of the labyrinth over a delay of seconds, a delay of 15 minutes, a delay of 1 hour, a delay of 2 hours, a delay of 6 hours, a delay of 24 hours or more. After a period of that delay, the subject is returned to the central platform (with previously blocked barriers to the track removed) and rewarded for the rest of the food during this trial memorization period. It is possible. Which track is blocked and its placement will change from trial to trial. Track the number of "errors" that the subject makes during the memorization inspection period. If the subject enters the track where food has already been recovered in the component prior to the delay time of the trial, or if the subject revisits the track already visited in the session after the delay time. An error occurs in the trial. A smaller number of errors may suggest better spatial memory. The number of errors made by the test subject in the treatment regimen of the various test compounds can then be compared to the effectiveness of the test compound in the treatment of cognitive impairment associated with CNS disorders.

Another cognitive test that can be used to evaluate the effect of test compounds on cognitive impairment in CNS-impaired model animals is the Maurice Water Maze. A water maze is a pool surrounded by a new pattern set for the maze. Training protocols for the water maze can be based on a modified water maze task that has been shown to be hippocampal-dependent (de Hoz et al., Eur. J. Neurosci., 22: 745-54, 2005; Steele and Morris, Hippocampus). 9: 118-36, 1999). Train the subject to locate the escape platform submerged in the water hidden beneath the surface of the pool. During the training trial, the subject is released into the maze (pool) from a random starting position around the pool. The starting position changes with each trial. If the subject does not locate the escape platform within the set time, the experimenter guides the subject to the platform and places it on the platform in order to "teach" the location of the platform. After a period of delay after the last training attempt, a memorization test is performed in the absence of the escape platform to evaluate spatial memory. For example, when the mouse is measured by the amount of time it spends at a (now nonexistent) escape platform location or the number of times it traverses that location, the subject's priority level for that location is better spatial memory, ie cognition. Suggest treatment for the disorder. The priority for the location of the escape platform under different treatment conditions can then be likened to the effectiveness of the test compound in the treatment of cognitive impairment associated with CNS disorders.

There are various tests known in the art for assessing cognitive function in humans, including, for example, the Clinical General Impression Change Scale (CIBIC-plus Scale); Mini-Mental State Examination (MMSE); Neuropsychological Symptoms. Assessment (NPI); Clinical Dementia Scale (CDR); Cambridge Neuropsychological Examination Battery (CANTAB); Sand Geriatric Clinical Assessment (SCAG), Buschke and Fill, 1974; Verbal Pairs Union Subtest; Logical Memory Subtest; Wechsler Memory Test Revised Edition (WMS-R) Visual Reproduction Subtest (Wechsler, 1997); Benton Visual Retention Test, or Work Memory, Processing Speed, Attention, Language Learning, Visual MATRICS consensus neuropsychological test batteries including, but not limited to, learning, reasoning and problem solving as well as social cognitive tests. Folstein et al., J Psychological Res 12: 189-98, (1975); Robbins et al., Dementia 5: 266-81, (1994); Rey, L'examen clinic en psychology, (1964); 12: 168-79, (1999); see Marquis et al., 2002 and Masur et al., 1994. Buchanan, R.M. W. , Keefe, R.M. S. E. , Umbricht, D.I. , Green, M. et al. F. , Laughren, T. et al. , And Marder, S.A. R. (2011) The FDA-NIMH-MATRICS guidelines for clinical trial design of cognitive-enhancing drags: what do we know 5 years later? Schizophr. Bull. See also 37,1209-1217. Another example of a cognitive test in humans is the explicit three-limb forced selection method. This test presents the subject with a color photograph of a mundane object consisting of a mixture of three types of image pairs: similar pairs, identical pairs and unrelated files. The second pair of similar objects is called a "bait". These image pairs are completely randomized and presented one by one as a series of images. Instruct the subject to determine if the object they see is new, old, or similar. The "similar" response to the presentation of the decoy stimulus suggests a successful memory search by the subject. In contrast, considering decoy stimuli as "old" or "new" suggests that correct memory retrieval did not occur.

By assessing surrogate changes in the subject's brain in addition to assessing cognitive performance, age-related cognitive impairment and progression of dementia and conversion from age-related cognitive impairment to dementia are monitored. obtain. Substitute changes include changes in local brain volume, degradation of penetrating fibers, and changes seen in brain function through resting fMRI (R-fMRI) and fluorodeoxyglucose positron emission tomography (FDG-PET). Not limited to these. Examples of local brain volume useful in monitoring age-related cognitive impairment and the progression of dementia include a decrease in hippocampal volume and a decrease in entorhinal cortex volume or thickness. These volumes can be measured in the subject, for example by MRI. Aisen et al., Alzheimer's & Dementia 6: 239-246 (2010). Degradation of penetrating fibers has been shown to be associated with age as well as decline in cognitive function. For example, older people with more penetrating fiber degradation tend to have poorer hippocampal-dependent memory test results. Degradation of penetrating fibers can be monitored in the subject through ultra-high resolution diffusion tensor imaging (DTI). Yassa et al., PNAS 107: 12687-12691 (2010). Resting fMRI (R-fMRI) is a large-amplitude, spontaneous low-frequency (<0) of the fMRI signal that images the resting brain and is temporarily correlated between functionally related regions. .1Hz) Includes recording fluctuations. By using seed-based functional binding, signal independent component analysis and / or frequency domain analysis, functional binding between brain regions, especially between regions where their binding increases or weakens with age. , And the degree of cognitive impairment and / or dementia are revealed. FDG-PET uses FDG uptake as a measure of local metabolic activity in the brain. Decreased FDG uptake in areas such as the posterior cingulate cortex, the temporal parietal cortex and the frontal association area has been shown to be associated with a degree of cognitive decline and dementia. Aisen et al., Alzheimer's & Dementia 6: 239-246 (2010), Herholz et al., NeuroImage 17: 302-316 (2002).

Age-related cognitive impairment The present invention relates to α5-containing GABA _A receptor positive allosteric modulators (ie, compounds of the invention) (eg, compounds as described herein or pharmaceutically acceptable salts thereof, water). Methods and compositions for treating age-related cognitive impairment or its risk using Japanese products, solvent products, polymorphs, isomers or combinations thereof are provided. In certain embodiments, treatment comprises preventing or delaying the progression of age-related cognitive impairment. In certain embodiments, treatment comprises alleviating, ameliorating or delaying the progression of one or more of the symptoms associated with age-related cognitive impairment. In certain embodiments, treatment of age-related cognitive impairment involves delaying the conversion of age-related cognitive impairment (including but not limited to MCI, ARCD and AAMI) to dementia (eg, AD). .. The methods and compositions can be used for human patients in clinical applications in treating age-related cognitive impairment or its risk in medical conditions such as MCI, ARCD and AAMI. The doses of the compositions and the dosing intervals for the methods are safe and effective in their application as described herein. In some embodiments of the invention, methods are provided for preserving or ameliorating cognitive function in a subject with age-related cognitive impairment, the method of which is a therapeutically effective amount of a compound of the invention to said subject. Alternatively, it comprises the step of administering a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof.

In some embodiments, subjects treated with the methods and compositions of the invention exhibit or are at risk of age-related cognitive impairment. In some embodiments, age-related cognitive impairment includes, but is not limited to, age-related memory impairment (AAMI), mild cognitive impairment (MCI) and age-related cognitive decline (ARCD).

Animal models serve as an important tool for developing and assessing treatments for such age-related cognitive impairment. The features that characterize age-related cognitive impairment in animal models usually extend to age-related cognitive impairment in humans. Therefore, efficacy in such animal models is expected to predict efficacy in humans.

Various animal models of age-related cognitive impairment are known in the art. For example, large-scale behavioral characterization identified a naturally occurring form of cognitive impairment in non-inbreeding species of aged Long-Evans rats (Charles River Laboratories; Gallagher et al., Behav. Neurosci. 107: 618. -626, (1993)). In behavioral assessments using the Maurice Water Maze (MWM), rats learn and remember the location of escape platforms guided by the placement of spatial cues surrounding the maze. The cognitive basis of performance of this ability is examined in probe trials using the measurement of animal spatial bias in locating escape platforms. Elderly rats in the study population can swim to a visible platform, but hiding the platform and seeking the use of spatial information detects age-dependent dysfunction. Performance of non-inbred Long-Evans strains on individual aged rats varies widely. For example, a proportion of those rats will perform as well as young adults. However, approximately 40-50% are outside the range of younger grades. This variation between older rats reflects reliable individual differences. Therefore, within the aged population, some animals have cognitive impairment and are pointed out as aging disorders (AI), while others are undisturbed and pointed out as aged-unimpaired (AU). To. For example, Colombo et al., Proc. Natl. Acad. Sci. 94: 14195-14199, (1997); Gallagher and Burwell, Neurobiol. Aging 10: 691-708, (1989); Gallagher et al., Behave. Neurosci. 107: 618-626 (1993); Rapp and Gallagher, Proc. Natl. Acad. Sci. 93: 9926-9930, (1996); Neuroscience 74: 741-756, (1996); Nicolle et al., J. Mol. Neurosci. 19: 9604-9610, (1999); see International Patent Publication WO2007 / 019312 and International Patent Publication WO2004 / 048551. Animal models of such age-related cognitive impairment can be used to assay the effectiveness of the methods and compositions of the invention in the treatment of age-related cognitive impairment.

The effectiveness of the methods and compositions of the invention in the treatment of age-related cognitive impairment can be assessed using various cognitive tests, including the Maurice water maze and radial maze as discussed herein.

Dementia The present invention relates to α5-containing GABA _A receptor positive allosteric modulators (eg, compounds as described herein or pharmaceutically acceptable salts thereof, hydrates, solvates, polymorphs, isomers, isomers). Methods and compositions for treating dementia using (selecting from the body or combination) are also provided. In certain embodiments, treatment comprises preventing dementia or delaying the progression of dementia. In certain embodiments, treatment comprises alleviating, ameliorating or delaying the progression of one or more symptoms associated with dementia. In certain embodiments, the symptom being treated is cognitive impairment. In some embodiments of the invention, methods are provided for preserving or ameliorating cognitive function in a subject with dementia, the method of which is a therapeutically effective amount of a compound of the invention or a pharmaceutical agent thereof for the subject. Includes the step of administering a generally acceptable salt, hydrate, solvate, polymorph, isomer or combination. In certain embodiments, the dementia is Alzheimer's disease (AD), vascular dementia, Lewy body dementia or corticobasal degeneration. The methods and compositions can be used for human patients in clinical applications in treating dementia. The doses of the compositions and the dosing intervals for the methods are safe and effective in their application as described herein.

Animal models serve as an important tool for developing and assessing treatments for dementia. The characteristics that characterize dementia in animal models usually extend to dementia in humans. Therefore, efficacy in such animal models is expected to predict efficacy in humans. Various animal models of dementia are known in the art, such as PDAPP, Tg2576, APP23, TgCRND8, J20, hPS2 Tg and APP + PS1 transgenic mice. Sankaranarayanan, Curr. Top. Medical Chem. 6: 609-627, 2006; Kobayashi et al., Genes Brain Behave. 4: 173-196.2005; She and Zahns, Neuron. 66: 631-45, 2010. Such animal models of dementia can be used to assay the effectiveness of the methods and compositions of the invention in the present invention in the treatment of dementia.

The effectiveness of the methods and compositions of the invention in treating dementia or cognitive disorders associated with dementia is as discussed herein using various cognitive tests known in the art for dementia. Can be evaluated in animal models as well as human subjects with dementia.

Post-traumatic stress disorders The present invention relates to α5-containing GABA _A receptor positive allosteric modulators (eg, compounds as described herein or pharmaceutically acceptable salts thereof, hydrates, solvates, polymorphs). , Which are selected from isomers or combinations) are also provided for methods and compositions for treating post-traumatic stress disorder (PTSD). In certain embodiments, treatment comprises preventing PTSD or delaying the progression of PTSD. In certain embodiments, treatment comprises alleviating, ameliorating or delaying the progression of one or more of the symptoms associated with PTSD. In certain embodiments, the symptom being treated is cognitive impairment. In some embodiments of the invention, methods are provided for preserving or ameliorating cognitive function in a subject having PTSD, wherein the method is to the subject in a therapeutically effective amount of a compound of the invention or a pharmaceutical thereof. Includes the step of administering an acceptable salt, hydrate, solvate, polymorph, isomer or combination to. The methods and compositions can be used for human patients in clinical applications when treating PTSD. The doses of the compositions and the dosing intervals for the methods are safe and effective in their application as described herein.

Patients with PTSD (and patients without lesser but less traumatically exposed PTSD) have a smaller hippocampal volume (Woon et al., Prog. Neuro-Psychopharm. & Biological Psych. 34, 1181-1188). Wang et al. Arch. Gen. Psychiatry 67: 296-303, 2010). PTSD is also associated with impaired cognitive ability. Elderly individuals with PTSD have a greater decline in cognitive ability than control patients (Yehuda et al., Bio. Psych. 60: 714-721, 2006) and are more likely to develop dementia (Yaffe et al., Arch). Gen. Psych. 678: 608-613, 2010).

Animal models serve as an important tool for developing and assessing treatment for PTSD. The characteristics that characterize PTSD in animal models usually extend to PTSD in humans. Therefore, efficacy in such animal models is expected to predict efficacy in humans. Various animal models of PTSD are known in the art.

One of the rat models of PTSD is time-dependent sensitization (TDS). TDS includes its prior stress situational reminder after the animal has been exposed to a severe stress event. The following is an example of TDS. Rats are restrained and then placed in a swim tank and allowed to swim for a period of time, eg, 20 minutes. Immediately after this, each rat is exposed to gas anesthetic until unconscious and finally dried. Keep the animals calm for several days, eg, a week. The rats are then exposed to a "restress" session consisting of the first stressor, eg, a swimming session in a swim tank (Liberzon et al., Psychopharmacology 22: 443-453, 1997; Harbury et al., Psychopharmacology 175: 494-502, 2004). TDS results in enhanced auditory startle response (ASR) in the rat, comparable to the exaggerated auditory startle that is a prominent symptom of PTSD (Khan and Liberzon, Psychopharmacology 172: 225-229, 2004). By using such an animal model of PTSD, the effectiveness of the methods and compositions of the invention in the treatment of PTSD can be assayed.

The effectiveness of the methods and compositions of the invention in treating PTSD or cognitive disorders associated with PTSD is as discussed herein in animals of PTSD using various cognitive tests known in the art. It can also be evaluated in models as well as in human subjects with PTSD.

Schizophrenia and Bipolar Disorder The present invention further relates to α5-containing GABA _A receptor positive allosteric modulators (eg, compounds as described herein or pharmaceutically acceptable salts, hydrates, solvates thereof). Methods and compositions for treating schizophrenia or bipolar disorder (particularly mania) using a substance, polymorph, isomer or combination) are provided. In certain embodiments, treatment involves prevention of schizophrenia or bipolar disorder (particularly mania) or delay in its progression. Schizophrenia is a positive symptom, eg, an abnormal or distorted psychotic representation (eg, illusion, delusion), or a symptom associated with dopamine dysregulation (eg, hyperdopaminergic response, hyperdopaminergic activity). Negative symptoms characterized by sexual behavioral responses, dopaminergic hyperactivity or hypervolatility or psychosis), diminished motivation and decreased adaptive target-oriented behavior (eg, avolition, flat plate of emotion). It is characterized by a wide range of psychopathology, including schizophrenia) and cognitive impairment. In certain embodiments, treatment comprises reducing, recovering or delaying the progression of one or more positive and / or negative symptoms and cognitive impairment associated with schizophrenia. In addition, there are several other psychiatric disorders such as schizotypal and schizoaffective disorders, other acute and chronic psychiatric disorders, and bipolar disorders (particularly mania), which are present. , Has a general medical condition that overlaps with schizophrenia. In some embodiments, treatment includes one or more symptoms associated with bipolar disorder (particularly mania) as well as alleviation, recovery or delay in its progression of cognitive impairment. In some embodiments of the invention, methods are provided for preserving or ameliorating cognitive function in a subject with schizophrenia or bipolar disorder, the method of which is a therapeutically effective amount of the invention to the subject. Includes the administration of a compound of or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof. The methods and compositions can be used for human patients in clinical applications in the treatment of schizophrenia or bipolar disorder (particularly mania). The doses of the compositions and the dosing intervals for the methods are safe and effective in their application as described herein.

Cognitive impairment is associated with schizophrenia. Cognitive deficits precede the development of psychosis and appear in unaffected relatives. Cognitive deficits associated with schizophrenia constitute a good predictor for functional outcomes and are a central feature of this disorder. The cognitive features of schizophrenia reflect dysfunction of the frontal cortex and hippocampal circuits. Patients with schizophrenia also exhibit hippocampal pathology, such as decreased hippocampal volume, decreased neuronal size, and dysfunctional hyperactivity. An imbalance between excitement and inhibition in these brain regions has also been demonstrated in patients with schizophrenia, suggesting that drugs targeting the inhibition mechanism may be therapeutic. For example, Guidotti et al., Psychopharmacology 180: 191-205, 2005; Zierhut, Psych. Res. Neuroimag. 183: 187-194, 2010; Wood et al., NeuroImage 52: 62-63, 2010; Vinkers et al., Expert Opin. Investig. Drugs 19: 1217-1233, 2009; Young et al., Pharmacol. The. 122: 150-202, 2009.

Animal models serve as an important tool for developing and assessing treatments for schizophrenia. The characteristics that characterize schizophrenia in animal models usually extend to schizophrenia in humans. Therefore, efficacy in such animal models is expected to predict efficacy in humans. Various animal models of schizophrenia are known in the art.

One animal model of schizophrenia is long-term treatment with methionine. Mice treated with methionine showed inadequate expression of GAD67 in the frontal cortex and hippocampus, similar to that reported in the brains of postmortem schizophrenic patients. These mice also exhibit astonishing prepulse inhibition and defects in social interactions (Tremonlizzo et al., PNAS, 99: 17095-17100, 2002). Another animal model of schizophrenia is methylazoxymethanol acetate (MAM) treatment in rats. MAM (20 mg / kg, intraperitoneal) is administered to pregnant female rats on the 17th day of pregnancy. MAM treatment reproduces the pathological process leading to schizophrenia-like phenotypes (including anatomical changes, behavioral defects and changes in neuronal information processing) in the offspring. More specifically, rats treated with MAM show low density parvalbumin-positive GABAergic interneurons in the prefrontal cortex and parts of the hippocampus. In behavioral studies, rats treated with MAM show reduced latent inhibition. Potential suppression is a behavioral phenomenon that reduces learning about pre-exposed stimuli with arbitrary consequences. This tendency to downplay previous benign stimuli and weaken the formation of associations with such stimuli is thought to prevent sensory overload. Low potential suppression implies psychosis. Potential inhibition can be tested in rats in the following manner: Divide the rats into two groups. One group is previously exposed to one type of sound over multiple trials. No sound is presented to the other group. Both groups are then exposed to an auditory fear conditioning procedure, in which the same sound is presented at the same time as a noxious stimulus, eg, an electric shock to the foot. Subsequently, the sounds are presented to both groups and the changes in the locomotor activity of those rats are monitored during the presentation of the sounds. After that fear conditioning, those rats respond to their sound presentation by strongly reducing their locomotor activity. However, the group exposed to the sound prior to the conditioning period shows strong potential suppression: the suppression of locomotor activity in response to the presentation of the sound is reduced. In contrast, rats treated with MAM show impaired potential suppression. That is, exposure to the sound prior to the fear conditioning procedure does not significantly affect the suppression of fear conditioning (see Rodge et al., J. Neurosci., 29: 2344-2354, 2009). Using such animal models of schizophrenia, the effectiveness of the methods and compositions of the invention in the treatment of schizophrenia or bipolar disorder (particularly mania) can be assayed.

Rats treated with MAM show a significantly enhanced locomotor response (or abnormal locomotor activity) to low doses of D-amphetamine. Rats treated with MAM also show a significant increase in the number of ventral tegmental dopamine (DA) neurons that spontaneously fire. These results were increased by inactivating the ventral hippocampus (vHip) in MAM-treated rats (eg, by intravHip administration of the sodium channel blocker tetrodotoxin (TTX) to MAM rats). It is believed to be the result of excessive hippocampal activity, as the activity of the DA neuron population was completely reversed and the increased amphetamine-induced locomotor behavior was normalized. The correlation between hippocampal dysfunction and excessive sensitivity of the DA system is believed to underpin an enhanced response to amphetamines in psychosis in MAM-treated animals and schizophrenic patients. Rodge D. J. Et al., Neuroscience of Disease (2007), 27 (42), 11424-11430. The use of MAM-treated rats in the above studies may be suitable for use in assaying the efficacy of the methods and compositions of the invention in the treatment of schizophrenia or bipolar disorder (particularly mania). For example, the methods and compositions of the invention use MAM-treated animals for control of the ventral hippocampus (vHip), increased DA neuronal population activity and amphetamines in MAM-treated animals. Their effect on hyperactive locomotor responses can be assessed.

In rats treated with MAM, hippocampal (HPC) dysfunction leads to hyperactivity of the dopamine system. Selective benzodiazepine against SH-053-2'F-R-CH ₃ is α5 subunit of the GABA _A receptor - positive allosteric modulators (PAM) is tested for effects on the output of the hippocampus (HPC). Effect of SH-053-2'F-R-CH ₃ against locomotor hyperactivity response to amphetamine in animals treated with MAM is also examined. α5GABAAR PAM was saline solution to the number of spontaneously active DA neurons in the ventral tegmental area (VTA) of MAM rats, both when administered systemically and when injected directly into the ventral HPC. Reduce to levels observed in treated rats (control group). In addition, HPC neurons in both saline-treated and MAM-treated animals show reduced cortical-induced responses after α5GABAAR PAM treatment. Furthermore, the increase in locomotor activity response to amphetamine observed in rats treated with MAM is reduced after α5GABA _A R PAM treatment. Gill K. See M et al., Neuropsychopharmacology (2011), 1-9. The use of rats treated with MAM in the above studies is to be used in the present invention to assay the effectiveness of the methods and compositions of the invention in the treatment of schizophrenia or bipolar disorder (particularly mania). May be suitable for For example, the methods and compositions of the invention can be evaluated using MAM-treated animals for their effects on hippocampal (HPC) output and hyperkinetic response to amphetamines in MAM-treated animals.

Administration of MAM to pregnant rats on embryonic day 15 (E15) seriously impairs their ability to learn spatial memory or the spatial location of four items on an eight-way radial maze in their offspring. In addition, rats treated with MAM on embryonic day 17 (E17) can reach the performance levels of control rats in the early stages of training, but spatially with a 30 minute delay inserted. The inability to process and remember the information suggests a significant dysfunction of working memory. Gourevitch R. Et al. (2004). Behave. See Pharmacol, 15, 287-292. Using such animal models of schizophrenia, the effectiveness of the methods and compositions of the invention in the treatment of schizophrenia or bipolar disorder (particularly mania) can be assayed.

Apomorphine-induced climbing behavior (AIC) and apomorphine-induced stereotyped behavior (AIS) in mice are other animal models useful in the present invention. The agent is administered to the mice at the desired dose level (eg, by intraperitoneal administration). Subsequently, for example, after 30 minutes, the experimental mice are administered with apomorphine (eg, 1 mg / kg, sc). Five minutes after apomorphine injection, apomorphine-induced sniffing-licking-gnawing syndrome (stereotyped behavior) and climbing behavior are scored and recorded for each animal. Judgment can be repeated every 5 minutes during a 30 minute examination session. For each syndrome (stereotyped and climbing behavior), add up the scores for each animal during the 30-minute test session. If the effect reaches at least 50% inhibition, the ID ₅₀ value (95% confidence interval) is calculated using the nonlinear least squares calculation by inverse prediction. The average climbing behavior score and the average stereotyped behavior score are expressed as percentages of the control values observed in mice treated with apomorphine and treated with vehicle (eg, saline). obtain. Glauer S. M. Et al., Psychopharmacology (2009) 204, 37-48. Using this mouse model, the effectiveness of the methods and compositions of the invention in the treatment of schizophrenia or bipolar disorder (particularly mania) can be assayed.

In another well-established preclinical model of schizophrenia, rats chronically exposed to the non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine are psychotic positive. It develops symptoms and negative symptoms as well as cognitive impairment. Ketamine (30 mg / kg, twice daily) is injected intraperitoneally in Long-Evans male rats over 2 weeks of adolescence (2 months of age). When rats reach adulthood (approximately 4-5 months of age), rat behavioral tests are performed on behavioral symptoms to ketamine exposure and the effectiveness of treatments to alleviate those symptoms. See, for example, Enomoto et al., Progress in Neuro-Psychiatrycology & Biological Psychiatry 33 (2009) 668-675.

The effectiveness of the methods and compositions of the invention in the treatment of schizophrenia or its associated cognitive impairment is as discussed herein using various cognitive tests known in the art for schizophrenia. Alternatively, it can be evaluated in animal models of bipolar disorder (particularly mania) as well as in human subjects with schizophrenia.

Amyotrophic lateral sclerosis (ALS)
The invention further comprises an α5-containing GABA _A receptor positive allosteric modulator (eg, a compound as described herein or a pharmaceutically acceptable salt, hydrate, solvate, polyform, isomer thereof). Or the method and composition for treating ALS using one selected from the combination). In certain embodiments, treatment comprises preventing ALS or delaying its progression. In certain embodiments, treatment comprises alleviating, ameliorating or delaying the progression of one or more of the symptoms associated with ALS. In certain embodiments, the symptom being treated is cognitive impairment. In some embodiments of the invention, methods are provided for preserving or ameliorating cognitive function in a subject having ALS, wherein the method is to the subject in a therapeutically effective amount of a compound of the invention or a pharmaceutical thereof. Includes the step of administering an acceptable salt, hydrate, solvate, polymorph, isomer or combination to. The methods and compositions can be used for human patients in clinical applications when treating ALS. The doses of the compositions and the dosing intervals for the methods are safe and effective in their application as described herein.

In addition to degeneration of motor neurons, ALS is characterized by neurodegeneration in the entorhinal cortex and hippocampus, memory deficiency, and increased neuronal excitability in different brain regions such as the cortex.

The effectiveness of the methods and compositions of the invention in treating ALS or cognitive disorders associated with ALS is an animal model of ALS using various cognitive tests known in the art, as discussed herein. It can also be evaluated in human subjects with ALS.

Cancer Treatment-Related Cognitive Disorders The present invention further relates to α5-containing GABA _A receptor positive allosteric modulators (eg, compounds as described herein or pharmaceutically acceptable salts, hydrates, solvates thereof). Methods and compositions for treating cancer treatment-related cognitive impairment using substances, polymorphs, isomers or combinations) are provided. In certain embodiments, treatment comprises preventing or delaying the progression of cancer treatment-related cognitive impairment. In certain embodiments, treatment comprises alleviating, ameliorating, or delaying the progression of one or more symptoms associated with cancer treatment-related cognitive impairment. In some embodiments of the invention, methods are provided for preserving or ameliorating cognitive function in a subject with cognitive impairment associated with cancer treatment, the method of which is a therapeutically effective amount of the present invention to the subject. Includes the administration of a compound of or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof. The methods and compositions can be used for human patients in clinical applications in treating cognitive impairment associated with cancer treatment. The doses of the compositions and the dosing intervals for the methods are safe and effective in their application as described herein.

Treatments used in the treatment of cancer, including chemotherapy, irradiation or combinations thereof, can cause cognitive impairment of functions such as memory, learning and attention of the patient. Cytotoxicity and other adverse side effects of cancer treatment on the brain are the basis for this form of cognitive impairment, which can last for decades (Dietrich et al., Oncologist 13: 1285-95, 2008; Soussine). Et al., Lancet 374: 1639-51, 2009).

Cognitive impairment after cancer treatment reflects dysfunction of the frontal cortex and hippocampal circuits that are essential for normal cognition. In animal models, exposure to either chemotherapy or radiation adversely affects the performance of these brain systems, especially hippocampal-specific cognitive tests (Kim et al., J. Radiat. Res. 49: 517-526,2008; Yang et al., Neurobiol. Learning and Mem. 93: 487-494, 2010). Therefore, these drugs that target the cortical and hippocampal systems can be neuroprotective in patients receiving cancer treatment and are a sign of cognitive impairment that can continue beyond the interventions used to treat cancer. Can be effective in treatment.

Animal models serve as an important tool for developing and assessing treatments for cancer treatment-related cognitive impairment. The characteristics that characterize cancer treatment-related cognitive impairment in animal models usually extend to cancer treatment-related cognitive impairment in humans. Therefore, efficacy in such animal models is expected to predict efficacy in humans. Various animal models of cancer treatment-related cognitive impairment are known in the art.

Examples of animal models of cancer treatment-related cognitive impairment include treatment of animals with antitumor agents such as cyclophosphamide (CYP) or irradiation, eg, ⁶⁰ Co gamma rays (Kim et al., J. Radiat). Res. 49: 517-526, 2008; Yang et al., Neurobiol. Learning and Mem. 93: 487-494, 2010). The cognitive function of an animal model of cancer treatment-related cognitive impairment can then be tested using cognitive tests that assay the effectiveness of the methods and compositions of the invention in the treatment of cancer treatment-related cognitive impairment. As discussed herein, the effectiveness of the methods and compositions of the invention in the treatment of cancer treatment-related cognitive impairment and cancer treatment-related cognitive impairment using various cognitive tests known in the art. Human subject with.

Parkinson's disease (PD)
Parkinson's disease (PD) is a neuropathy characterized by decreased voluntary movement. Patients suffering from this have less motor activity and slower voluntary movements than normal individuals. Patients have a characteristic "mask-like" facial appearance, a tendency to rush while walking, a crooked posture and systemic weakness of the muscles. There is a typical "leadpipe-like" rigidity of passive motion. Another important feature of the disease is limb tremor, which occurs at rest and decreases during exercise.

Parkinson's disease has an unknown etiology and belongs to the most common group of movement disorders named Parkinsonism, affecting approximately 1 in 1000 people. These other disorders, classified by the name Parkinsonism, may result from viral infections, syphilis, arteriosclerosis and trauma, as well as exposure to harmful chemicals and narcotics. Nevertheless, it is believed that improper loss of synaptic stability can lead to neural circuit disruption and brain disease. Neuronal communication dysfunction, whether as a result of heredity, substance use, aging processes, viral infections or a variety of other causes, is believed to be the root cause of many neurological disorders such as PD. (Myrrh van Spronsen and Casper C. Hoogenrad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214).

Regardless of the cause of the disease, the main pathological feature is the degeneration of dopaminergic cells in the basal ganglia, especially in the substantia nigra. Due to premature death of dopamine-containing neurons in the substantia nigra, the largest structure of the basal ganglia, the striatum can reduce input from the substantia nigra, resulting in reduced dopamine release. Understanding the underlying pathology led to the introduction of the first successful treatment that could alleviate Parkinson's disease. Virtually all approaches to the treatment of this disease are based on dopamine substitution. The drugs currently used in this procedure can be converted to dopamine after crossing the blood-brain barrier, or can boost dopamine synthesis and reduce its degradation. Unfortunately, cell degeneration in the substantia nigra, a major pathological event, cannot be helped. As the disease continues to progress, dopamine replacement treatments often lose their effectiveness after a period of time.

The present invention relates to α5-containing GABA _A receptor positive allosteric modulators (eg, compounds as described herein or pharmaceutically acceptable salts, hydrates, solvates, polyforms, isomers or isomers thereof. Methods and compositions for treating PD using (selected from combinations) are provided. In certain embodiments, treatment comprises preventing PD or delaying its progression. In certain embodiments, treatment comprises alleviating, ameliorating or delaying the progression of one or more symptoms associated with PD. In certain embodiments, the symptom being treated is cognitive impairment. For example, the methods and compositions of the present disclosure can be used to ameliorate motor / cognitive deficits that represent Parkinson's disease. In addition, the methods and compositions of the present disclosure may be useful for treating memory deficits that represent Parkinson's disease. In some embodiments of the invention, methods are provided for preserving or ameliorating cognitive function in a subject having PD, the method of which is a therapeutically effective amount of a compound of the invention or a pharmaceutical thereof to the subject. Includes the step of administering an acceptable salt, hydrate, solvate, polymorph, isomer or combination to.

There are several animal models of PD. Exemplary PD animal models include reserpine model, methanefetamine model, 6-hydroxydopamine (6-OHDA) model, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model, Examples include a paraquat (PQ) -Maneb model, a rotenone model, a 3-nitrotyrosine model and a genetic model using transgenic mice. Transgenic models include mice that overexpress α-synuclein and express human variants of α-synuclein, or mice that express the LRKK2 mutation. Ranjita B. See an overview of these models by Ranjita B. et al., BioEssays 2002, 24, 308-318. For more information on these animal models, see Jackson Laboratories (see also http: //research.jax.org/grs/parkinsons.html) and numerous publications disclosing the use of these validated models. It is easily available from.

The effectiveness of the methods and compositions of the invention in the treatment of PD or PD-related cognitive impairment is described herein using various cognitive tests known in the art of the above PD. It can be evaluated in any of the animal models as well as in human subjects with PD.

Autism Autism is a neurodevelopmental disorder characterized by dysfunction in three central behavioral dimensions: repetitive behavior, social deficiencies and agnosia. Areas of repetitive behavior include compulsive behavior, unusual attachment to objects, adherence to routines or rituals, and repetitive motor mannerism such as stereotyped and self-stimulating behavior. The dimensions of social deficiencies include deficiencies in reciprocal social interactions, lack of eye contact, poor ability to continue conversation, and impaired daily interaction skills. Agnosia can also include language abnormalities. Autism is a disability-causing neuropathy that affects thousands of Americans, includes several subtypes, has various putative causes, and few remission treatments have been reported. No. Disorders of the autism spectrum may be present at birth and may later develop, for example, at the age of two or three. There are no clear biological markers for autism. Diagnosis of this disorder is made by considering the degree to which the child matches a behavioral syndrome characterized by poor communication skills, peculiarities of social and cognitive abilities, and maladapted behavioral patterns. Neuronal communication dysfunction is believed to be one of the root causes of autism (Myrrh van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214). .. _{Recent studies have shown that GABA A} α5 defects are present in autism spectrum disorders (ASD) and support further studies of the GABA system in this disorder (Mendez MA et al., Neuropharmacology. 2013, 68). : 195-201).

The present invention relates to α5-containing GABA _A receptor positive allosteric modulators (eg, compounds as described herein or pharmaceutically acceptable salts, hydrates, solvates, polyforms, isomers or isomers thereof. Methods and compositions for treating autism using (selected from combinations) are also provided. In certain embodiments, treatment comprises preventing autism or delaying its progression. In certain embodiments, treatment comprises alleviating, ameliorating or delaying the progression of one or more of the symptoms associated with autism. In certain embodiments, the symptom being treated is cognitive impairment or agnosia. For example, the methods and compositions of the present disclosure can be used to ameliorate movement disorders / agnosia representing autism. In some embodiments of the invention, methods are provided for preserving or ameliorating cognitive function in a subject having autism, wherein the method is to the subject in a therapeutically effective amount of a compound of the invention or a method thereof. It comprises the step of administering a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination.

The valproic acid (VPA) rat model of autism (Rodier, PM et al., Reprod. Toxicol. 1997, 11, 417-422) using in vitro electrophysiological techniques established by Rodier et al. Is the most comprehensive. One of the established autism injury-based animal models, pregnant women treated with VPA in the 1960s have higher autism than the normal population in a limited time frame for embryogenesis. Based on the observation that he was at risk of giving birth to a child. Pregnant rat births exposed to VPA have some anatomical and behavioral symptoms specific to autism (eg, low numbers of cerebellar purkineruneurons, impaired social interaction). Other symptoms of autism, including presence, repetitive behavior, and enhanced processing of fear memory). Rinaldi T. See Frontiers in Neural Circuits, 2008, 2, 1-7. Another mouse, an established model with robust behavioral patterns associated with three diagnostic behavioral symptoms of autism: unusual social interactions, impaired communication and repetitive behavior. Model BTBR T + tf / J (BTBR) mice were used to explore the efficacy of the selective negative allosteric modulator GRN-529 for the mGluR5 receptor. For example, Silverman J. et al. L. Et al., Sci Transl. Med. See 2012, 4, 131. The effectiveness of the methods and compositions of the invention in the treatment of autism or autism-related agnosia is discussed herein using various cognitive tests known in the art. It can be evaluated in a rat model of autism treated with VPA or a BTBR T + tf / J (BTBR) mouse model, as well as a human subject with autism.

Mental retardation Mental retardation is a general disorder characterized by severely impaired cognitive function and adaptive behavioral deficiencies. Mental retardation is often defined as an IQ score of less than 70. Congenital causes are many root causes of mental retardation. Neuronal communication dysfunction is also thought to be one of the root causes of mental retardation (Myrrh van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214). ..

In some cases, mental retardation includes Down syndrome, palatal cardio-facial syndrome, fetal alcohol syndrome, fragile X syndrome, Kleinfelder syndrome, neurofibromatosis, congenital hypothyroidism, Williams syndrome, phenylketonuria ( PKU), Smith Remli Opitz Syndrome, Prader Willy Syndrome, Ferran McDermid Syndrome, Mowat Wilson Syndrome, Ciliary Diseases, Law Syndrome and Siderium-type X-Chain Mental Retardation, but not limited to these. Down's syndrome is a disorder that includes a combination of some degree of mental retardation, characteristic facial features, and often heart defects, many infections, visual and hearing problems, and birth defects, including other health problems. Fragile X syndrome is a common form of hereditary mental retardation that occurs in 1 in 4,000 men and 1 in 8,000 women. The syndrome is also characterized by stunted growth, hyperactivity, attention deficit disorder and autism-like behavior. There is no effective treatment for Fragile X Syndrome.

The present invention contemplates the treatment of mild mental retardation, moderate mental retardation, severe mental retardation, severe mental retardation and mental retardation of unknown severity. Such mental retardation may be associated with, but is not limited to, chromosomal changes (eg, Down's syndrome due to trisomy 21), genetics, pregnancy and perinatal problems and other severe mental disorders. The present invention relates to α5-containing GABA _A receptor positive allosteric modulators (eg, compounds as described herein or pharmaceutically acceptable salts, hydrates, solvates, polyforms, isomers or isomers thereof. Methods and compositions for treating mental retardation using (choose from combinations) are provided. In certain embodiments, treatment comprises preventing mental retardation or delaying its progression. In certain embodiments, treatment comprises alleviating, ameliorating or delaying the progression of one or more of the symptoms associated with mental retardation. In certain embodiments, the symptom being treated is agnosia / dysfunction. For example, the methods and compositions of the present disclosure can be used to ameliorate motor / cognitive disorders that represent mental retardation. In some embodiments of the invention, methods are provided for preserving or ameliorating cognitive function in a subject with mental retardation, the method of which is a therapeutically effective amount of a compound of the invention or a pharmaceutical agent thereof for the subject. Includes the step of administering a generally acceptable salt, hydrate, solvate, polymorph, isomer or combination.

Several animal models have been developed for mental retardation. For example, a knockout mouse model has been developed for Fragile X Syndrome. Fragile X syndrome is a common form of mental retardation due to the absence of the FMR1 protein FMRP. Two homologs of FMRP, FXR1P and FXR2P, have been identified. FXR2P, like FMRP, is highly expressed in the brain and testis. Both Fxr2 knockout mice and Fmr1 knockout mice and Fmr1 / Fxr2 double knockout mice are considered to be useful models for mental retardation such as Fragile X Syndrome. Bontekoe C.I. J. M. Et al., Hum. Mol. Genet. 2002, 11 (5): See 487-498. The effectiveness of the methods and compositions of the invention in the treatment of mental retardation or mental retardation-related disability / cognitive impairment is as discussed herein using various cognitive tests known in the art. , These mouse models and other animal models developed for mental retardation, as well as human subjects with mental retardation can be evaluated.

Compulsive behavior (obsessive-compulsive disorder)
Obsessive-compulsive disorder (“OCD”) is most commonly an intrusive repetitive unnecessary thought (compulsion) that results in an individual feeling forced to act (compulsion), compulsion and mental behavior. It is a mental state characterized by. Current epidemiological data indicate that OCD is the fourth most common mental illness in the United States. Many studies with this disorder suggest that the prevalence of OCD is 1-3 percent, but clinically recognized prevalence of OCD is lower. It is suggested that the individual may not have been diagnosed. Patients with OCD should be a psychologist, psychiatrist or psychiatrist according to the diagnostic criteria of the Digital and Statistical Manual of Mental Disorders, 4th edition text revision (DSM-IV-TR) (2000), including the features of obsessive-compulsive and compulsive. Often diagnosed by scholars. Obsessive-compulsive features include (1) repetitive and persistent thoughts, impulses or thoughts that are experienced as intrusive and cause significant anxiety or distress; (2) those thoughts, impulses or thoughts are real-life problems. Not just excessive anxiety about; and (3) the person attempts to ignore or prevent such thoughts, urges or thoughts, or neutralize them with some other thought or act. Trying to do so. The person recognizes that obsessive thoughts, impulses or thoughts are a product of his or her mind and are not based on reality. The characteristics of coercion are (1) repetitive or mental behavior that the person feels compelled to do in response to a certain compulsion or according to rules that must be strictly applied; (2) that behavior. Or the mental behavior is intended to prevent or reduce or prevent some fearful events or situations; however, these behaviors or mental behaviors are not really related to the problem. Or it may be excessive.

Individuals with OCD usually perform a task (or coercion) to seek relief of obsessive-compulsive anxiety. Often, repetitive actions (eg, hand washing, counting, confirmation or washing) are performed with the desire to prevent or eliminate obsessive-compulsive thoughts. However, performing these "rituals" merely provides temporary relief. People with OCD can also be diagnosed with a series of other psychiatric disorders such as generalized anxiety disorder, anorexia nervosa, panic attacks or schizophrenia.

Neuronal communication dysfunction is believed to be one of the root causes of obsessive-compulsive disorder (Myrrh van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214). Studies suggest that OCD may be associated with abnormal levels of a neurotransmitter called serotonin. The first-line treatment of OCD consists of behavioral therapy, cognitive therapy and drug therapy. The agent for treatment, a serotonin reuptake inhibitor (SRI) (e.g., paroxetine ^(Seroxat TM, Paxil ^{(TM), Xetanor TM, ParoMerck TM,} Rexetin TM), sertraline (Zoloft (TM), Stimuloton ^TM ), Fluvoxetine (Prozac®, Bioxetin ^TM ), escitaloplum (Lexapro®) and fluvoxamine (Luvox®) and tricyclic antidepressants, in particular Chromipramine (Anafranil®). Benzodiazepine is also used in the procedure, however, as many as 40-60% of patients do not respond adequately to SRI treatment, and even more proportion of patients do not completely relieve their symptoms.

The present invention relates to α5-containing GABA _A receptor agonists (eg, α5-containing GABA _A receptor positive allosteric modulators) (eg, compounds as described herein or pharmaceutically acceptable salts and hydrates thereof). A method and composition for treating OCD using a hydrate, polymorph, isomer or combination) is provided. In certain embodiments, treatment comprises preventing OCD or delaying its progression. In certain embodiments, treatment comprises alleviating, ameliorating or delaying the progression of one or more of the symptoms associated with OCD. In certain embodiments, the symptom being treated is cognitive impairment or agnosia. For example, the methods and compositions of the present disclosure can be used to treat agnosia in OCD and / or to improve cognitive function in patients with OCD. In some embodiments of the invention, methods are provided for preserving or ameliorating cognitive function in a subject having an OCD, wherein the subject is given a therapeutically effective amount of a compound of the invention or a pharmaceutical thereof. Includes the step of administering an acceptable salt, hydrate, solvate, polymorph, isomer or combination to.

A kinpyrol sensitized rat model has been developed for OCD. The obsessive-compulsive confirmation behavior, which is a characteristic peculiar to OCD compulsion behavior, of this kinpyrol sensitized rat tends to be interrupted. In addition, the effect of the novel 5-HT2C receptor agonist WAY-163909 was evaluated using a schedule-induced polydipsia (SIP) rodent model of obsessive-compulsive disorder. For example, Rosenzweig-Lipson S. et al. Et al., Psychopharmacology (Beller) 2007,192,159-70. The effectiveness of the methods and compositions of the invention in the treatment of OCD or OCD-related cognitive impairment or agnosia is described above using various cognitive tests known in the art, as discussed herein. It can be evaluated in animal models and other animal models developed for OCD as well as human subjects with OCD.

Substance addiction Material addiction (eg, drug addiction, alcohol addiction) is a mental disorder. Material addiction is not triggered instantly when exposed to a substance of abuse. Rather, this substance addiction requires the adaptation of multiple complex neurons that occur over time, ranging from hours to days to months (Kauer JA Nat. Rev. Neurosci. 2007,8,844-858). The path to substance addiction is usually the voluntary use of one or more regulatory substances (eg, any of narcotics, barbiturates, methamphetamine, alcohol, nicotine and various other such regulatory substances). start from. Sustained use of these regulators over a long period of time impairs the voluntary ability to refrain from those regulators due to the effects of long-term use on brain function and hence behavioral effects. .. Therefore, substance addiction is usually characterized by obsessive-compulsive substance cravings, exploration and use that persist despite negative consequences. That desire can correspond to the underlying neurobiological changes in the patient, which must probably be addressed in a meaningful way if recovery is to be achieved. Material addiction is often also characterized by life-threatening withdrawal symptoms (eg, alcohol, barbiturates) in some cases and, in other cases, substantial morbidity (nausea, vomiting, fever). , May include dizziness and heavy sweating), can result in diminished ability to obtain distress and recovery. For example, alcoholism, also known as alcoholism, is one such substance addiction. Alcoholism is primarily characterized by four symptoms, including desire, loss of control, physical dependence and tolerance. These symptoms can also characterize substance addiction to other regulated substances. The desire for alcohol and other regulated substances is often as strong as the desire for food or water. Therefore, alcoholics may continue to drink despite significant family, health and / or legal side effects.

Recent studies investigating the effects of substance abuse on the central nervous system (CNS) have demonstrated various adverse effects on mental health, including substance-induced cognitive dysfunction. rice field. Nyberg F. See Cognitive Impairments in Drug Addictions, Chapter 9. In some laboratories and clinics, substantial damage to brain function is believed to be due to these drugs. The adverse effects of substance of abuse on the brain are associated with accelerated degeneration. Observations that have received particular attention in recent years are that chronic drug users show overt dysfunction in brain regions associated with executive function and memory function. The stated neuroadaptations caused by indulgence (eg, alcohol, central stimulants and opiates) include a decrease in neurogenesis in the hippocampal subgranular zone (SGZ). In fact, it has been proposed that reduced adult neurogenesis in SGZ may alter hippocampal function to be involved in recurring and maintaining addictive behavior. It also increases the likelihood that reduced neurogenesis may be involved in the agnosia induced by these abused drugs.

The present invention relates to α5-containing GABA _A receptor positive allosteric modulators (eg, compounds as described herein or pharmaceutically acceptable salts, hydrates, solvates, polyforms, isomers or isomers thereof. (Selected from combinations) are used to provide methods and compositions for treating substance addictions. In certain embodiments, treatment involves prevention of substance addiction or delay in its progression. In certain embodiments, treatment comprises alleviating, ameliorating or delaying the progression of one or more symptoms associated with substance addiction. In certain embodiments, the symptom being treated is cognitive impairment. For example, the methods and compositions of the present disclosure can be used to treat cognitive impairment and / or improve cognitive function in patients with substance addiction. In some embodiments of the invention, methods are provided for preserving or ameliorating cognitive function in a subject having material addiction, wherein the method is to the subject in a therapeutically effective amount of a compound of the invention or a pharmaceutical product thereof. Includes the step of administering a generally acceptable salt, hydrate, solvate, polymorph, isomer or combination.

Several animal models have been developed to study substance addiction. To study the neurobiology of alcoholism, for example, a genetically selected Marchigan Sardinian alcohol preference (msP) rat model has been developed. Cicocioppo R. Et al., Substation Addiction Biology 2006, 11, 339-355. The effectiveness of the methods and compositions of the invention in treating substance addiction or cognitive disorders associated with substance addiction is as discussed herein using various cognitive tests known in the art. Can also be evaluated in animal models and human subjects with substance addiction.

Research Domain Criteria (RDoC)
The present invention further provides, as described herein, .alpha.5-containing GABA A _R positive allosteric modulators or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or a combination It is used to provide methods and compositions for treating neuropathy and dysfunction of neuropsychiatric conditions. In certain embodiments, treatment comprises alleviating, ameliorating or delaying the progression of one or more of the symptoms associated with such dysfunction. In another aspect of the invention, the compound of the invention or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof may be used to preserve or improve cognitive function. Methods and compositions for preserving or ameliorating cognitive function in a subject are provided.

Research Domain Criteria (RDoC) are expected to enhance clinical criteria such as DSM and ICD for diagnosing diseases and disorders affecting the nervous system (see, eg, Am. J. Psychiatry 167: 7 (2010)). That). RDoC aims to provide classification methods based on findings and clinical findings in genomics and neuroscience. _{High expression of α5-containing GABA A} receptors in special neural circuits of the nervous system can be therapeutic targets for neural circuit dysfunction identified under RDoC.

The affinity of GABA _A .alpha.5 test compound to GABA _A receptors containing the assay GABA _A .alpha.5 subunit for subunit binding and receptor positive allosteric modulator activity can be measured using known receptor binding assays in the art. See, for example, US Pat. No. 7,642,267 and US Pat. No. 6,743,789, which are incorporated herein by reference.

α5 activity containing GABA A _R test compounds as positive allosteric modulators may be tested by known electrophysiological methods in the art. See, for example, US Pat. No. 7,642,267 and Guidotti et al., Psychopharmacology 180: 191-205, 2005. Positive allosteric modulator activity can be tested, for example, by assaying the GABA-induced chlorine ion conductance of _{GABA A receptors containing the GABA A} α5 subunit. Cells expressing such receptors can be exposed to effective amounts of the compounds of the invention. Such cells may come into contact with the compounds of the invention in vivo by contact with body fluids containing the compounds of the invention, eg, with cerebrospinal fluid. In vitro tests can be performed by contacting cells with the compounds of the invention in the presence of GABA. Increased GABA-induced chlorine ion conductance in the presence of the test compound in cells expressing the _{GABA A} receptor containing the GABA _{A α5 subunit may suggest positive allosteric modulator activity of the compound.} Such changes in conductance include, for example, Xenopus egg mother cells injected with _{GABA A} receptor subunit mRNA (including GABA _A α5 subunit RNA), HEK293 transfected with a plasmid encoding the _{GABA A receptor subunit.} It can be detected by using a voltage fixation assay performed on cells, or in vivo, exobibo or cultured neurons.

The methods described herein can be adapted and modified as appropriate for the application undertaken, and the methods described herein can be used in other suitable applications. It will be appreciated by those skilled in the art that what can be done, and such other additions and modifications, do not deviate from the scope of the invention.

The present invention will be better understood from the following examples. However, one of ordinary skill in the art will readily recognize that the particular methods and results discussed are merely embodiments of the invention that are more fully described in embodiments that follow.

スキーム１１．

０℃のＨＣｌ（濃、３９ｍＬ）中の５−メトキシ−２−ニトロアニリン（５ｇ，２９．７ｍｍｏｌ）の撹拌混合物に、Ｈ_２Ｏ（１９ｍＬ）中のＮａＮＯ_２（２．０５ｇ，２９．７ｍｍｏｌ）の溶液を滴下により添加した。内部温度を１０℃未満に維持した。添加後、その混合物を室温において１時間撹拌した。ジアゾニウム塩を濾過によって回収し、次の工程において使用した。室温において高速撹拌した状態の結晶化皿内のそのジアゾニウム塩に、Ｈ_２Ｏ（７ｍＬ）中のＮａＮ_３（１．９３ｇ，２９．６ｍｍｏｌ）の溶液を滴下により添加した。ガス発生が止んだ後（３時間）、それを濾過した。回収された固体をＭｅＯＨから再結晶することにより、４．３４２ｇ（２工程について収率７５％）の生成物１３を黄色固体として得た。室温のＥｔＯＨ（４０ｍＬ）中の、フェニルアジド１３（１．９４ｇ，１０ｍｍｏｌ）とジエチル１，３−アセトン−ジカルボキシレート（ｄｉｅｔｈｙｌ １，３−ａｃｅｔｏｎｅ−ｄｉａｃｒｂｏｘｙｌａｔｅ）（２．２０ｍＬ，１２ｍｍｏｌ）との混合物に、Ｅｔ_３Ｎ（１．６７ｍＬ，１２ｍｍｏｌ）を添加した。その混合物を室温において６０時間撹拌した後、最初の懸濁物は、透明な黄色溶液になった。その溶液を減圧下で濃縮し、残渣をクロマトグラフィー（ＲｅｄｉＳｅｐ２４ｇシリカ−ゲルカラム，ヘキサン中１０％〜４０％のＥｔＯＡｃ）によって精製することにより、２．９０５ｇのトリアゾール１４を黄色固体として得た。ＭＳ：［Ｍ＋１］＝３７９。 Example 1: Synthesis of Compound 1

Scheme 11.

0 ℃ of HCl (conc., 39 mL) solution of 5-methoxy-2-nitroaniline (5 g, 29.7 mmol) to a stirred mixture _of, H 2 O (19mL) NaNO in ₂ (2.05g, 29.7mmol) Solution was added by dropping. The internal temperature was maintained below 10 ° C. After the addition, the mixture was stirred at room temperature for 1 hour. The diazonium salt was recovered by filtration and used in the next step. The diazonium salt in the crystallization dish while high speed stirring at room _{temperature, NaN} 3 _{(1.93g, 29.6mmol)} in H 2 O (7mL) was added dropwise. After the gas generation stopped (3 hours), it was filtered. The recovered solid was recrystallized from MeOH to give 4.342 g (75% yield for 2 steps) of product 13 as a yellow solid. Mixture of phenyl azide 13 (1.94 g, 10 mmol) in EtOH (40 mL) at room temperature with diethyl 1,3-acetone-diacrboxyllate (2.20 mL, 12 mmol). _in, it was added Et 3 N (1.67mL, 12mmol) . After stirring the mixture at room temperature for 60 hours, the first suspension became a clear yellow solution. The solution was concentrated under reduced pressure and the residue was purified by chromatography (RediSep 24 g silica-gel column, 10% -40% EtOAc in hexanes) to give 2.905 g of triazole 14 as a yellow solid. MS: [M + 1] = 379.

Pd / C (10wt%, 407mg , 0.38mmol) above triazole 14 (2.95 g, 7.66 mmol) in EtOH (50 mL) containing a stirred _{H 2} (balloon) for 24 hours under. It was filtered through Celite. The filtrate was concentrated and the residue was purified by chromatography (RediSep 24 g silica-gel column, 10% -50% EtOAc in hexanes) to give 2.453 g of aniline 15 as a white solid (70% for 2 steps). yield). MS: [M + 1] = 349.

Compound 15 (2.45 g, 7.03 mmol) in p-xylene (30 mL) and a catalytic amount of p-TsOH · H ₂ O (24 mg) were heated overnight in an oil bath at 140 ° C. The mixture was cooled and filtered. The solid was washed with cold EtOAc. After drying, 1.88 g (88% yield) of lactam 16 was obtained. MS: [M + 1] = 303.

_{LiBH 4} (2M in THF, 1.39 mL, 2.78 mmol) was added to a suspension of lactam ester 16 (837 mg, 2.77 mmol) in THF (20 mL) at room temperature. The mixture was stirred at room temperature for 60 hours, then additional LiBH ₄ (2M in THF, 0.28 mL, 0.56 mmol) was added and it was stirred at room temperature for an additional 24 hours. A mixture of EtOAc / EtOH (10 mL / 10 mL) was added to the reaction and concentrated under reduced pressure. The residue was dissolved in EtOAc / CH ₂ Cl ₂ / MeOH and coarse silica gel was added. After evaporating the volatile solvent, the solid was loaded into a RediSep 24g silica-gel column. Chromatography (solvent A: EtOAc, solvent B: 10: 1 v / v CH ₂ Cl ₂ / MeOH; eluent gradient: A to B) gave 540 mg (75% yield) of alcohol 17 as a white solid. .. MS: [M + 1] = 261.

A solution of alcohol 17 (105.4 mg, 0.40 mmol) and CBr _{4 (336 mg, 1.01 mmol) in DMF (3 mL) plus a solution of PPh 3} (255 mg, 0.97 mmol) in DMF (1 mL). It was added slowly over 20 minutes. After the addition, TLC showed that the reaction was complete. The reaction was quenched by the addition of water and the mixture was extracted 3 times with EtOAc. The combined extracts _H 2 O, successively washed with brine and dried over _Na 2 SO _4. Crude products were obtained by filtration and concentration. Chromatography - by (RediSep12g silica gel _{column, CH 2 Cl 2 ~CH 2 Cl} 2 in a 30% EtOAc), to give a mixture of 439.2mg of bromide 18 ([M + 1] = 324) and _Ph 3 PO. Pd / C (10wt%, 200mg , 0.19mmol) EtOAc / EtOH (8mL / 8mL) above mixture in (439 mg) _{H 2} (balloon) was stirred for 2 hours under containing, then filtered through celite. The filtrate is concentrated and the residue is purified by chromatography (RediSep 12g silica-gel column, solvent A: 1: 1 v / v CH ₂ Cl ₂ / hexane, solvent B: EtOAc; eluent gradient: A to B). 99 mg (about 80% yield for 2 steps) of product 19 was obtained as a white solid. MS: [M + 1] = 245.

After treating 1,2,3-triazole (55.3 mg, 0.80 _{mmol) in CH 3} CN (1 mL) at 0 ° C. _{with i-Pr 2} NEt (146 μL, 0.84 mmol) in a separate flask. , POCl ₃ (23 μL, 0.25 mmol). The solution was stirred at 0 ° C. for 2 hours. Lactam 19 was added all at once and the resulting suspension was heated in an oil bath at 80 ° C. for 20 hours. The reaction was quenched by the addition of water. It was extracted 3 times with EtOAc. The combined extracts were washed with brine and dried over Na ₂ SO ₄ . Filtration and concentration gave 48.8 mg of crude product 20, which was used as is in the next step. A solution of KO-t-Bu (37.2 mg, 0.33 mmol) in DMF (0.5 mL) was cooled to −50 ° C. Ethyl acetate (40 μL, 0.36 mmol) was added dropwise. The mixture was stirred at −50 ° C. for 1 hour. The crude product 20 in DMF (1 mL) was added dropwise. The mixture was heated to 10 ° C. and stirred at 10 ° C. for 1 hour. The addition of saturated aqueous _NH 4 Cl and it was extracted 3 times with EtOAc. The combined extracts were washed successively with water and brine and dried over Na ₂ SO ₄ . Crude products were obtained by filtration and concentration.

15 mg (for 2 steps) by chromatography (RediSep 12 g silica-gel column, solvent A: 1: 1 v / v CH ₂ Cl ₂ / hexane, solvent B: EtOAc; eluent gradient: 20% -80% B in A). Compound 1 (Example 1) with a yield of 21%) was obtained as an off-white solid. MS: [M + 1] = 340. ¹ H-NMR (500MHz, CDCl3) δ: 7.74 (s, 1H), 7.63 (d, 1H, J = 3Hz), 7.51 (d, 1H, J = 8.5Hz), 7.14 (dd, 1H, J = 3.0) , 8.5Hz), 4.44 (q, 2H, J = 7.0Hz), 3.95 (s, 3H), 2.44 (s, 3H), 1.45 (t, 3H, J = 7.0Hz).
Example 2: Synthesis of Compound 2:

Compound 2 is made into a light brown solid by synthesizing the compound of Example 2 using 5-fluoro-2-nitro-aniline as a starting material in a synthetic route similar to that described in Example 1. Obtained: MS: [M + 1] = 328. ¹ H-NMR (500MHz, CDCl3) δ: 7.90 (br dd, 1H, J = 2.5, 8.5Hz), 7.77 (s, 1H), 7.62 (br dd, 1H, J = 5.0, 9.0Hz), 7.35 ( m, 1H), 4.45 (q, 2H, J = 7.0Hz), 2.45 (s, 3H), 1.45 (t, 3H, J = 7.0Hz).
Example 3: Synthesis of Compound 3:

Compound 3 was obtained as a pale yellow solid by synthesizing the compound of Example 3 using 2-nitro-aniline as a starting material in a synthetic pathway similar to that described in Example 1: MS. : [M + 1] = 310; ¹ H-NMR (500MHz, CDCl3) δ: 8.161 (br d, 1H, J = 8.5Hz), 7.81 (s, 1H), 7.66 (m, 3H), 4.45 (q, 2H) , J = 7.0Hz), 2.45 (s, 3H), 1.46 (t, 3H, J = 7.0Hz).
Example 4: Synthesis of compound 110

The acetamide oxime was azeotroped with toluene three times before use. A 60% NaH dispersion in oil (16 mg, 0.4 mmol) was added to the suspension of acetamide oxime (30 mg, 0.4 mmol) in THF (1 mL). The suspension was stirred at room temperature for 15 minutes. Ester compound 2 (65 mg, 0.2 mmol) was added. The vial containing the ester was rinsed with THF (1 mL) and added to the reaction mixture. The resulting brown suspension was stirred at room temperature for 30 minutes and then heated at 70 ° C. for 2 hours and 30 minutes. The suspension was quenched with MeOH. The solvent was evaporated and the crude oil was purified by chromatography (RediSep 4g silica-gel column, eluted with 70% EtOAc in hexanes) to give 28 mg (41% yield) of product. MS: [M + 1] = 338. H ¹ NMR (CDCl ₃ ) δ7.92 (1H, dd, J = 2.5, 8.5Hz), 7.90 (1H, s), 7.67 (1H, dd, J = 4.5, 9.5Hz), 7.38 (1H, m) , 2.51 (3H, s), 2.46 (3H, s).
Example 5: Synthesis of compound 167

実施例６：化合物４の合成：

The compound was similarly prepared from compound 1 to give compound 167: MS: [M + 1] = 350. H ¹ NMR (CDCl ₃ ) δ7.87 (1H, s), 7.65 (1H, d, J = 3Hz), 7.55 (1H, d, J = 9Hz), 7.17 (1H, dd, J = 2.5, 9Hz) , 3.96 (3H, s), 2.5 (3H, s), 2.45 (3H, s).
Scheme 12.

Example 6: Synthesis of Compound 4:

_{After adding Et 3} N (0.7 mL, 5 mmol) to a solution of compound 17 (260 mg) prepared as in Example 1 in DMSO (4 mL) and CH ₂ Cl _{2 (6 mL), Py.} SO ₃ (398 mg, 2.5 mmol) was added. It was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted 3 times with EtOAc. The combined extracts _H 2 O, successively washed with brine and dried over _Na 2 SO _4. Filtration and concentration gave 198.5 mg of crude aldehyde 21, which was used without further purification. PhMgBr (1M in THF, 1.54 mL, 1.54 mmol) was added dropwise to a suspension of aldehyde 21 (198.5 mg, 0.77 mmol) in THF (10 mL) at 0 ° C. It was stirred at 0 ° C. for 30 minutes. The addition of saturated aqueous _NH 4 Cl and it was extracted 3 times with EtOAc.

The combined extracts were washed with brine and dried over Na ₂ SO ₄ . Filtration and concentration gave 252.9 mg of benzyl alcohol 22 as a brown foam solid. It was used in the next step without further purification. TFA (0.64 mL, 8.27 mmol) was added to the solution of the crude alcohol 22 in _{CH 2} Cl ₂ (8 mL) containing Et ₃ SiH (0.60 mL, 3.76 mmol). The reaction solution was stirred at room temperature for 4 hours. After concentration, the residue was purified by chromatography (RediSep 12 g silica-gel column, 20% -80% EtOAc in hexanes) to whiten 34.1 mg (12% yield for 4 steps) of reduced product 23. Obtained as a foamy solid. MS: [M + 1] = 321.

In a separate flask, a solution of 1,2,4-triazole (27 mg, 0.39 _{mmol) in CH 3 CN (0.5 mL) at 0 ° C. was treated with i-Pr 2} NEt (72 μL, 0.41 mmol). After that, _{it was treated with POCl 3} (11 μL, 0.12 mmol). The mixture was stirred at 0 ° C. for 2 hours. Lactam material 23 (32.2 mg, 0.1 mmol, solid) was added to the reaction mixture at once and heated in an oil bath at 80 ° C. for 20 hours. When the mixture was cooled to room temperature, a creamy solid precipitate was observed. Water (0.5 mL) was added and it was stirred at room temperature for 5 minutes. The solid precipitate was collected by filtration, washed with 0.5 mL of water and then dried under high vacuum to give 15.8 mg (42% yield) of adduct 24 as an off-white fluffy solid. Obtained. MS: [M + 1] = 372. A solution of KO-t-Bu (9.5 mg, 85 μmol) in DMF (0.5 mL) was cooled to −50 ° C. Ethyl acetate (10.4 μL, 95 μmol) was added dropwise. The resulting mixture was stirred at −50 ° C. for 1 hour. Triazole amidine 24 (15.8 mg, 42 μmol, solid) was added at once. The stirred mixture was heated to 10 ° C. over 1 hour and maintained at 10 ° C. for 1 hour. The addition of saturated aqueous _NH 4 Cl and it was extracted 3 times with EtOAc. The combined extracts _H 2 O, successively washed with brine and dried over _Na 2 SO _4. Crude products were obtained by filtration and concentration. 16.8 mg (yield) by chromatography (RediSep 4 g silica-gel column. Solvent A: 1: 1 v / v CH ₂ Cl ₂ / hexane, Solvent B: EtOAc; Eluent gradient: 50% B in A to A). The compound of Example 6 (95%) was obtained as a white solid. MS: [M + 1] = 416. ¹ H-NMR (500MHz, CDCl3) δ: 7.74 (s, 1H), 7.63 (d, 1H, J = 3.0Hz), 7.50 (d, 1H, J = 9.0Hz), 7.30 (br d, 2H, J) = 7.0Hz), 7.29 (br d, 2H, 7.5Hz), 7.20 (m, 1H), 7.13 (dd, 1H, J = 2.5, 9.0Hz), 4.41 (q, 2H, J = 7.5Hz), 4.17 (s, 2H), 3.95 (s, 3H), 1.43 (t, 3H, 7.5Hz).
Example 7: Synthesis of Compound 5:

Compound 5 was obtained as a brown solid by synthesizing the compound of Example 7 using 2-nitro-aniline as a starting material in a synthetic route similar to that described in Example 6: MS: [M + 1] = 386. ¹ H-NMR (500MHz, CDCl3) δ: 8.16 (br d, 1H, J = 7.0Hz), 7.81 (s, 1H), 7.60-7.68 (m, 3H), 7.34 (br d, 2H, J = 8.0) Hz), 7.29 (br d, 2H, J = 7.0Hz), 7.20 (m, 1H), 4.42 (q, 2H, J = 7.0Hz), 4.18 (s, 2H), 1.44 (t, 3H, J = 7.0Hz).
Example 8: Synthesis of Compound 6:

Compound 8 is obtained as a brown solid by synthesizing the compound of Example 8 using 5-fluoro-2-nitro-aniline as a starting material in a synthetic route similar to that described in Example 6. T: MS: [M + 1] = 404. ¹ H-NMR (500MHz, CDCl3) δ: 7.90 (dd, 1H, J = 3.5, 8.5Hz), 7.77 (s, 1H), 7.61 (dd, 1H, J = 5.0, 10.5Hz), 7.28-7.37 ( m, 5H), 7.21 (m, 1H), 4.43 (q, 2H, J = 7.0Hz), 4.17 (s, 2H), 1.44 (t, 3H, J = 7.0Hz).
Example 9: Synthesis of Compound 44:

The compound of Example 9 is browned by synthesizing the compound of Example 9 using 5-fluoro-2-nitro-aniline as a starting material in a synthetic route similar to that described in Example 6. Obtained as a brownish solid: MS: [M + 1] = 418. ¹ H-NMR (500MHz, CDCl3) δ: 7.89 (br d, 1H, J = 9.5Hz), 7.76 (s, 1H), 7.60 (dd, 1H, J = 5.5, 10.0Hz), 7.35 (br t, 1H, J = 6.0Hz), 7.22 (br d, 2H, J = 8.5Hz), 7.09 (br d, 2H, J = 7.5Hz), 4.43 (q, 2H, J = 7.5Hz), 4.12 (s, 2H), 2.30 (s, 3H), 1.44 (t, 3H, J = 7.5Hz).
Example 10: Synthesis of Compound 45:

The compound of Example 10 is browned by synthesizing the compound of Example 10 using 5-fluoro-2-nitro-aniline as a starting material in a synthetic route similar to that described in Example 6. Obtained as a brownish solid: MS: [M + 1] = 438. ¹ H-NMR (500MHz, CDCl3) δ: 7.90 (dd, 1H, J = 3.0, 8.0Hz), 7.77 (s, 1H), 7.61 (dd, 1H, J = 5.0, 9.0Hz), 7.36 (m, 1H), 7.25 (br s, 4H), 4.42 (q, 2H, J = 7.0Hz), 4.14 (s, 2H), 1.44 (t, 3H, J = 7.0Hz).
Example 11: Synthesis of Compound 46:

The compound of Example 11 is yellowed by synthesizing the compound of Example 11 using 5-fluoro-2-nitro-aniline as a starting material in a synthetic route similar to that described in Example 6. Obtained as a nitrous solid: MS: [M + 1] = 422. ¹ H-NMR (500MHz, CDCl3) δ: 7.90 (dd, 1H, J = 3.0, 8.5Hz), 7.77 (s, 1H), 7.61 (dd, 1H, J = 5.0, 9.0Hz), 7.36 (m, 1H), 7.28 (m, 2H), 6.96 (m, 2H), 4.42 (q, 2H, J = 7.5Hz), 4.14 (s, 2H), 1.44 (t, 3H, J = 7.0Hz).
Example 12: Synthesis of compound 47:

By synthesizing the compound of Example 12 using 2-nitro-aniline as a starting material in a synthetic route similar to that described in Example 6, the compound of Example 12 is made into a yellowish solid. Obtained: MS: [M + 1] = 420. ¹ H-NMR (500 MHz, CDCl3) δ: 8.16 (br d, 1H, J = 7.0Hz), 7.80 (s, 1H), 7.64 (m, 3H), 7.25 (m, 4H), 4.41 (q, 2H, J = 7.0Hz), 4.14 (s, 2H), 1.44 (t, 3H, J = 8.0Hz).
Example 13: Synthesis of compound 109:

Acetamide oxime (50 mg, 0.67 mmol) was azeotroped with toluene three times. THF (5 mL) was added, followed by 60% NaH dispersion in oil (25 mg, 0.62 mmol). The suspension was stirred at room temperature for 30 minutes. 2 mL of this suspension was added to ester compound 6 (40 mg, 0.099 mmol) and the resulting solution was heated at 70 ° C. for 3 hours. The solution was quenched with water. The solution was extracted with EtOAc (3 times). The combined organic phases were washed with brine, dried over MgSO _4. Crude products were obtained by filtration and concentration. Chromatography (RediSep 12 g silica-gel column, eluted with 50% EtOAc in hexanes) gave 6 mg (20% yield) of compound 109 as a yellow solid. MS: [M + 1] = 414). H ¹ NMR (CDCl ₃ ) δ7.93 (1H, dd, J = 3, 8.5Hz), 7.89 (1H, s), 7.65 (1H, dd, J = 5.5, 9Hz), 7.38 (1H, m), 7.23 (5H, m), 4.2 (2H, s), 2.50 (3H, s).
Example 14: Synthesis of Compound 7:

0 ℃ of HCl (conc. 12.9 mL) solution of 5-methoxy-2-nitroaniline (5 g, 29.7 mmol) to a stirred mixture _of, H 2 O (8mL) in a NaNO ₂ (2.05g, 29.7mmol ) Was added dropwise. The internal temperature was maintained below 5 ° C. After the addition, the mixture was warmed to room temperature over 1 hour. The mixture was cooled to 0 ° C., it was added a solution slowly dropwise and HCl SnCl ₂ · _{2H 2} O of (dark 13 mL) in (20.13g, 89.2mmol). After the addition, it was stirred at room temperature for 2 hours. The resulting yellow solid was collected by filtration and washed with cold (0 ° C.) 6N HCl. After drying in a vacuum oven, 3.245 g (50% yield) of brown solid was obtained as aryl hydrazine 25. MS: [M + H ₂ O + Na] = 224. In a separate flask, a mixture of diethyl 1,3-acetonediacrboxyl (2.426 g, 12 mmol) and diethoxymethyl acetate (1.946 g, 12 mmol) was microwave-irradiated. Was heated at 100 ° C. for 1 hour. The reaction mixture is concentrated under reduced pressure, and the remaining volatile components are removed by co-distilling with toluene (5 ml) under reduced pressure to obtain the condensation product 26, which is used as it is in the next step. did.
Scheme 13.

The product 26 from the above was dissolved in EtOH (30 mL). Molecular sieves (4 Å, 2 g) and hydrazine hydrochloride 25 (2.19 g, 10 mmol) were added. The suspension was stirred at room temperature for 24 hours. It was filtered through Celite and the solid was washed with EtOAc (10 mL x 3). The filtrate was concentrated. The residue was purified by chromatography (RediSep 40 g silica-gel column, 10% -40% EtOAc in hexanes) to give 2.091 g of pyrrole 27, which was used in the next step without further purification. MS: [M + 1] = 378.

The 27 (2.09 g, 5.5 mmol) of the nitro group on, _{H 2} (balloon) for 18 hours under was reduced Pd / C (10wt%, 295mg , 0.28mmol) in EtOH (40 mL) containing .. The mixture was filtered through Celite. The filtrate is concentrated and the residue is purified by chromatography (RediSep 24 g silica-gel column, 50% EtOAc in hexanes from hexanes) to result in 1.127 g of decyclization product 28 as a yellow sticky oil ([M + 1]. ] = 348) + 154 mg of cyclization product 29 (MS: [M + 1] = 302) as a gray solid. Acyclized aniline 28 (1.127 g, 3.2 mmol) in p-xylene (20 mL _{) was treated with a catalytic amount of p-TsOH · H 2} O (15 mg) in an oil bath at 140 ° C. for 20 hours. .. The reaction mixture was cooled, concentrated and the residue was triturated with cold (0 ° C.) EtOAc. Filtration gave 559 mg of lactam product 29 as a yellow solid. The total weight of the combined lactam product 29 is 713 mg (24% for 3 steps). MS: [M + 1] = 302.

Dival-H (1M in hexanes, 6.60 mL, 6.60 mmol) was added to a suspension of ester 29 (566 mg, 1.88 mmol) in _{CH 2} Cl ₂ (35 mL) at −78 ° C. The suspension was stirred at −78 ° C. for 10 minutes. The cold bath was removed and it was stirred for 20 minutes, during which time the temperature rose to room temperature. At this point, TLC showed that the reaction was about 80% complete. It was cooled to −78 ° C. and additional Dival-H (1M in hexanes, 1.0 mL, 1.0 mmol) was added. After stirring at −78 ° C. for 30 minutes, LCMS showed that the reaction had proceeded to completion. The reaction was quenched by the addition of EtOAc followed by aqueous Rochelle salt solution (20%). It was vigorously stirred at room temperature until a clear two-layer mixture was obtained. The layers were separated and the aqueous layer was extracted 3 times with EtOAc. The combined organic phases were washed with brine and dried over Na ₂ SO ₄ . Filtration and concentration gave 480 mg of crude alcohol 30 as a slightly yellow solid. MS: [M + 1] = 260.

A solution of alcohol 30 (200 mg, 0.77 mmol) and CBr _{4 (640 mg, 1.93 mmol) in DMF (8 mL) to a solution of PPh 3} (486 mg, 1.85 mmol) in DMF (2 mL) for 30 minutes. Slowly added over. After the addition, it was stirred at room temperature for 30 minutes. The reaction was quenched by the addition of water and the mixture was extracted 3 times with EtOAc. The combined extracts _H 2 O, successively washed with brine and dried over _Na 2 SO _4. Crude products were obtained by filtration and concentration. 221 mg of bromide 31 by chromatography (RediSep 12 g silica-gel column, solvent A: 1: 1 v / v CH ₂ Cl ₂ / hexane, solvent B: EtOAc; eluent gradient: 10% to 40% B in A). And Ph ₃ PO were obtained.

Pd / C (10wt%, 200mg , 0.19mmol) to EtOAc / EtOH (8mL / 8mL) above mixture containing the mixture was stirred for 1 hour at _{H 2} (balloon) below. It was filtered through Celite. The filtrate is concentrated and the residue is chromatographed (RediSep 12 g silica-gel column, solvent A: 1: 1 v / v CH ₂ Cl ₂ / hexane, solvent B: EtOAc; eluent gradient: 10% to 40% B in A). By purification with, 146 mg of a mixture of reduction product 32 ([M + 1] = 244) and Ph ₃ PO was obtained.

スキーム１４．

In a separate flask, 1,2,4-triazole (81 mg, 1.17 mmol) in _{CH 3 CN (1 mL) at 0 ° C. was treated with i-Pr 2} NEt (214 μL, 1.23 mmol) and then POCl. _{Treated with 3} (34 μL, 0.36 mmol). The solution was stirred at 0 ° C. for 2 hours. Lactam 32 (about 60% purity by LCMS) was added at one time and the resulting suspension was heated in an oil bath at 80 ° C. for 18 hours. The reaction was quenched by the addition of water. It was extracted 3 times with EtOAc. The combined extracts _H 2 O, successively washed with brine and dried over _Na 2 SO _4. Filtration and concentration gave 126.6 mg of crude product 33 as a yellow sticky product, which was used as is in the next step. MS: [M + 1] = 295. A solution of KO-t-Bu (97 mg, 0.86 mmol) in DMF (1 mL) was cooled to −50 ° C. Ethyl acetate (104 μL, 0.95 mmol) was added dropwise. The mixture was stirred at −50 ° C. for 1 hour. The crude product 33 in DMF (1.5 mL) was added dropwise. The mixture was heated to 10 ° C. and stirred at 10 ° C. for 1 hour. The addition of saturated aqueous _NH 4 Cl and it was extracted 3 times with EtOAc. The combined extracts were washed successively with water and brine and dried over Na ₂ SO ₄ . Crude products were obtained by filtration and concentration. Chromatography (RediSep 12 g silica-gel column, solvent A: 1: 1 v / v CH ₂ Cl ₂ / hexane, solvent B: EtOAc; eluent gradient: 10% to 40% B in A) to obtain a 22 mg white solid. Obtained and further purified by preparative TLC (developed at 1: 1 A / B) to give 12.8 mg of final product compound 7 (Example 14) as a white solid. MS: [M + 1] = 339. ¹ H-NMR (500MHz, CDCl3) δ: 7.70 (s, 1H), 7.56 (s, 1H), 7.50 (d, 1H, J = 3.0Hz), 7.43 (d, 1H, J = 8.5Hz), 7.00 (dd, 1H, J = 2.5, 9.5Hz), 5.29 (br s, 1H), 4.44 (q, 2H, J = 7.0Hz), 3.92 (s, 3H), 3.55 (br s, 1H), 2.17 ( s, 3H), 1.45 (t, 3H, J = 7.0Hz).
Example 15: Synthesis of Compound 8:

Scheme 14.

_{After adding Et 3} N (0.7 mL, 5 mmol) to the solution of alcohol 30 (261 mg, 1.0 mmol) prepared in Example 14 in DMSO (4 mL) and CH ₂ Cl _{2 (6 mL).} Py · SO ₃ (398 mg, 2.5 mmol) was added. It was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted 3 times with EtOAc. The combined extracts _H 2 O, successively washed with brine and dried over _Na 2 SO _4. Filtration and concentration gave 226 mg of crude aldehyde 34 as a yellow solid. It was used in the next step without purification. MS: [M + 1] = 258.

PhMgBr (1M in THF, 1.58 mL, 1.58 mmol) was added dropwise to a suspension of crude aldehyde 34 (202 mg, 0.79 mmol) in THF (10 mL) at 0 ° C. It was stirred at 0 ° C. for 30 minutes. The addition of saturated aqueous _NH 4 Cl and it was extracted 3 times with EtOAc. The combined extracts were washed with brine and dried over Na ₂ SO ₄ . Filtration and concentration gave 275 mg of crude product 35 as a yellow foam solid, which was used in the next step without purification.

TFA (0.70 mL, 9.02 mmol) was added to the solution of the crude alcohol 35 in _{CH 2} Cl ₂ (10 mL) containing Et ₃ SiH (0.66 mL, 4.10 mmol). The reaction solution was stirred at room temperature for 1 hour. After concentration, the residue was purified by chromatography (RediSep 24 g silica-gel column, 10% -50% EtOAc in hexanes) to give 187.8 mg (59% yield for 3 steps) product 36 as a gray solid. rice field. MS: [M + 1] = 320.

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In a separate flask, a solution of 1,2,4-triazole _{(127 mg, 1.83 mmol) in CH 3 CN (1.6 mL) at 0 ° C. was treated with i-Pr 2} NEt (336 μL, 1.93 mmol). After that, _{it was treated with POCl 3} (53 μL, 0.56 mmol). The mixture was stirred at 0 ° C. for 2 hours. Lactam 36 (150 mg, 0.47 mmol, solid) was added to the reaction mixture at once and heated in an oil bath at 80 ° C. for 18 hours. When the mixture was cooled to room temperature, a solid precipitate was observed. Water (2.1 mL) was added and it was stirred at room temperature for 10 minutes. The solid was filtered, washed with 2 mL of water and then dried under high vacuum to give 118.8 mg (69% yield) of triazole amidine 37 as an off-white fluffy solid. MS: [M + 1] = 371. A solution of KO-t-Bu (72 mg, 0.64 mmol) in DMF (2 mL) was cooled to −50 ° C. Ethyl acetate (77 μL, 0.71 mol) was added dropwise. The resulting mixture was stirred at −50 ° C. for 1 hour. Triazole amidine 37 (118.8 mg, 42 μmol, solid) was added in one lot. The stirred mixture was heated to 10 ° C. over 1 hour and maintained at 10 ° C. for 1 hour. The addition of saturated aqueous _NH 4 Cl and it was extracted 3 times with EtOAc. The combined extracts _H 2 O, successively washed with brine and dried over _Na 2 SO _4. By filtration, concentration, and then chromatography (RediSep 12 g silica-gel column. Solvent A: 1: 1 v / v CH ₂ Cl ₂ / Hexane, Solvent B: EtOAc; Eluent gradient: 40% B in A to A). 125.1 mg (yield 94%) of compound 8 was obtained as a white solid. MS: [M + 1] = 415. ¹ H-NMR (500 MHz; CDCl ₃ ) δ: 7.72 (s, 1H), 7.54 (s, 1H), 7.51 (br s, 1H), 7.44 (br d, 1H, J = 9.5Hz), 7.29 ( br d, 2H, J = 7.5Hz), 7.20 (m, 3H), 7, 01 (br d, 1H, J = 7.5Hz), 5.30 (br s, 1H), 4.38 (q, 2H, J = 7.0) Hz), 3.92 (br s, 5H), 3.54 (br s, 1H), 1.41 (t, 3H, J = 7.0Hz).
Example 16: Synthesis of Compound 9:

Scheme 15.

LiOH (1.09 g, 45.5 mmol) in a stirred solution of ester 16 (prepared in Example 1) (2.75 g, 9.10 mmol) in THF (24 mL) and water (20 mL) at room temperature. Added. MeOH (4 mL) was added and stirring was continued at room temperature for 2 hours, at which point LCMS showed complete consumption of the ester. When concentrated under reduced pressure, the reaction mixture was acidified to pH 3-4 by adding 2N HCl (20 mL). After stirring for 20 minutes, the reaction mixture is cooled to 0 ° C., the solid precipitate is collected by filtration, washed with 3-4 ml of water and dried to give 1.59 g (64%) of the corresponding acid. 38 was obtained as a grayish solid. MS: [M + 1] = 275. EDC (5.6 g, 29.2 mmol), benzyl alcohol (2.5 g, 23.2 mmol) and DMAP in acid 38 (1.59 g, 5.8 mmol) suspended and stirred in DCM (30 ml). (3.54 g, 29.2 mmol) was added. After stirring at room temperature for 3 days, the reaction was concentrated under reduced pressure. After adding water (80 mL) to the slurry, diethyl ether (40 mL) was added and the mixture was vigorously stirred for 40 minutes, at which point the slurry turned into a precipitate, which was collected by suction filtration. .. The solid was washed with water and a small amount of diethyl ether and dried to give 1.65 g (78%) of benzyl ester 39 as a white solid. MS: [M + 1] = 365.

Compounds 1,2,4-triazole (1.22 g, 17.7 _{mmol) in CH 3} CN (15 mL) at 0 ° C. were _{treated with i-Pr 2} NEt (3.24 mL, 18.6 mmol) and then POCl _3. It was treated with (0.507 mL, 5.44 mmol). The solution was stirred at 0 ° C. for 2 hours. Benzyl ester 39 (1.65 g, 4.53 mmol) was added all at once and the resulting suspension was heated in an oil bath at 80 ° C. for 18 hours. LCMS showed that 5-10% of the starting lactam remained. In separate flasks, _{1,2,4-triazole (307 mg, total 4.9 eq) in CH 3} CN (3.8 mL) at 0 ° C. for 2 hours, i-Pr ₂ Net (0.82 mL, total). It was treated with 5.1 eq) and POCl ₃ (0.127 ml; 1.5 eq total). The resulting clear solution was transferred to the reaction mixture. After heating at 80 ° C. for 2 hours, the reaction was cooled to room temperature and the reaction was quenched by the slow addition of water (10 minutes). After cooling in an ice bath, the solid formed was collected by filtration, washed with water (5 ml) and dried to give 1.61 g (86%) of product 40 as a pale yellow solid. MS: [M + 1] = 416.

A solution of KO-t-Bu (0.739 g, 6.59 mmol) in DMF (11 mL) was cooled to −50 ° C. Ethyl acetate (0.810 mL, 7.00 mmol) was added dropwise. The mixture was stirred at −50 ° C. for 1 hour. The above triazole intermediate 40 (1.61 g, 3.87 mmol) was added. The mixture was stirred at −50 ° C. for 30 minutes and slowly warmed to room temperature over 4-5 hours. Saturated NH ₄ Cl aqueous solution (10 mL) was added, followed by EtOAc (10 mL). The mixture was sonicated to break the solid mass and then stirred well for 30 minutes. The precipitate was collected by filtration _{, washed with water, Et 2} O and dried to give the crude product as a white solid. The filtrate was divided between water and EtOAc; the aqueous layer was separated and extracted twice with EtOAc; the combined EtOAc layers were washed with brine, dried over MgSO _4. Filtration and solvent removal yields a solid residue that is combined with the solid obtained above for chromatographic purification using a RediSep 24g silica-gel column and gradient elution with 0.5-5% MeOH in DCM. Thereby, 1.78 g (100%) of imidazole 41 was obtained as a white solid. MS: [M + 1] = 460. Hydrogenation decomposition of benzyl ester 41 (1.78 g, 3.87 mmol) in a solvent mixture of THF (40 mL), MeOH (20 mL) and EtOAc (20 mL) in the presence of a catalytic amount of 10% charcoal-supported Pd. It was subjected to a hydroxyl (hydrogen balloon) for 20 hours. LCMS showed that the starting material had completely disappeared. The solid catalyst was removed by filtration through Celite and rinsed repeatedly with a sufficient amount of 30% MeOH in DCM until almost all products were recovered (TLC monitor). The filtrate containing the product was concentrated under reduced pressure to give 1.22 g (85%) of the acid product 42 as a yellowish solid. MS: [M + 1] = 370.

A borane dimethyl sulfide complex (2M THF; 19 mL, 38 mmol) was added dropwise to the acid 42 (1.22 g, 3.30 mmol) suspended in THF (25 mL) at 0 ° C. and stirred. The ice bath was removed and the reaction mixture was stirred at room temperature for 16 hours. After cooling in an ice bath, the reaction was carefully quenched with MeOH (20 mL) and then stirred overnight at room temperature. The solvent was removed under reduced pressure. MeOH was added and removed twice more under reduced pressure. ISCO purification (RediSep 24 g column) with a gradient of 1-8% MeOH in DCM gave 0.625 g (53%) alcohol product 43 as a white solid. MS: [M + 1] = 356.

Diisopropyl azodicarboxylate (48.3 mg, 0.233 mmol), alcohol 43 (37.5 mg, 0.106 mmol), phenol (14.9 mg, 0.158 mmol) in anhydrous THF (0.8 mL) at 0 ° C. And Ph ₃ P (55.6 mg, 0.212 mmol) was added dropwise to a stirred solution. The ice bath was removed and stirring was continued at room temperature for 16 hours. LCMS showed that the starting alcohol had completely disappeared. The reaction mixture was divided into _{saturated NaHCO 3 and EtOAc.} The organic layer was separated, washed with water and brine and dried with י ₄ . The desired product is simply obtained from the reaction mixture by two consecutive preparative TLCs (4% MeOH in DCM and hexane / EtOAc / MeOH = 47.5 / 47.5 / 5, v / v / v). Separation gave 5.3 mg (12%) product of compound 9 as a white solid. MS: [M + 1] = 432. ¹ H-NMR (500 MHz, CDCl3) δ: 7.77 (s, 1H), 7.63 (d, 1H, J = 3.5Hz), 7.53 (d, 1H, J = 9.0Hz), 7.31 (m, 2H), 7.17 (dd, 1H, J = 3.0, 8.5Hz), 7.08 (d, 2H, J = 7.0Hz), 6.99 (t, 1H, J = 6.5Hz), 5.30 (s, 2H), 4.40 (q, 2H) , J = 7.0Hz), 3.96 (s, 3H), 1.38 (t, 3H, J = 7.0Hz).
Example 17: Synthesis of Compound 10:

Compound 10 (4.9 mg) is made into a white solid by synthesizing the compound of Example 17 using 4-fluoro-phenol in the last step in a synthetic route similar to that described in Example 16. Obtained as: MS: [M + 1] = 450. ¹ H-NMR (500 MHz, CDCl3) δ: 7.76 (s, 1H), 7.64 (d, 1H, J = 3.5Hz), 7.53 (d, 1H, J = 8.0Hz), 7.17 (dd, 1H, J) = 2.5, 8.0Hz), 7.01 (m, 4H), 5.26 (s, 2H), 4.40 (q, 2H, J = 7.0Hz), 3.96 (s, 3H), 1.40 (t, 3H, J = 7.0Hz) ).
Example 18: Synthesis of Compound 11:

Compound 11 (6.1 mg) is made into a white solid by synthesizing the compound of Example 18 using 3-methoxy-phenol in the last step in a synthetic route similar to that described in Example 16. Obtained as: MS: [M + 1] = 462. ¹ H-NMR (500 MHz, CDCl3) δ: 7.76 (s, 1H), 7.63 (d, 1H, J = 2.5Hz), 7.53 (d, 1H, J = 9.0Hz), 7.15-7.22 (m, 2H) ), 6.67 (m, 2H), 6.55 (br dd, 1H, J = 2.5, 8.0Hz), 5.28 (s, 2H), 4.39 (q, 2H, J = 7.0Hz), 3.96 (s, 3H), 3.81 (s, 3H), 1.39 (t, 3H, J = 7.0Hz).
Example 19: Synthesis of Compound 12:

Compound 12 (3.1 mg) is whitened by synthesizing the compound of Example 19 using 2,4-dimethylphenol in the last step in a synthetic route similar to that described in Example 16. Obtained as solid: MS: [M + 1] = 460. ¹ H-NMR (500 MHz, CDCl3) δ: 7.76 (s, 1H), 7.65 (d, 1H, J = 3.0Hz), 7.53 (d, 1H, J = 9.0Hz), 7.17 (dd, 1H, J) = 2.5, 8.5Hz), 6.98 (m, 3H), 5.26 (s, 2H), 4.37 (q, 2H, J = 7.0Hz), 3.96 (s, 3H), 2.26 (s, 3H), 2.20 (s) , 3H), 1.36 (t, 3H, J = 7.0Hz).
Example 20: Synthesis of Compound 107:

Phenol (30 mg, 0) in a solution of _{alcohol 43 with X = F (prepared in the same manner as in the examples with X = OCH 3} ) (60 mg, 0.17 mmol) in THF (0.8 mL). .32 mmol), triphenylphosphine (84 mg, 0.32 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes. It was then cooled using an ice bath and DIAD (64 μL, 0.32 mmol) in THF (0.2 mL) was added slowly. The ice bath was removed and the reaction mixture was stirred at room temperature for 18 hours. LCMS showed that some starting material was still present. Phenol (10 mg), triphenylphosphine (28 mg) and DIAD (21 μL) were added to the reaction mixture, and the mixture was further stirred for 1 hour. By evaporating the solvent and purifying the crude material by chromatography (RediSep 12g silica-gel column. Elution solvent: EtOAc) and preparative TLC (elution solvent: 5% MeOH / 47.5% EtOAc / 47.5% hexanes). Compound 107, which is a product of 11.4 mg (16% yield), was obtained. [M + 1] = 421). H ¹ NMR (CDCl ₃ ) δ7.92 (1H, dd, J = 3.5, 8.5Hz), 7.80 (1H, s), 7.63 (1H, dd, J = 5, 10Hz), 7.38 (1H, m), 7.31 (2H, t, J = 8.5Hz), 7.07 (2H, d, J = 8.5Hz), 7.00 (1H, t, J = 8.5Hz), 5.3 (2H, s), 4.39 (2H, q, J) = 7Hz), 1.38 (3H, t, J = 7Hz).
Example 21: Synthesis of Compound 111:

_{POBr 3} (405 mg, 1.41 mmol) was added to a suspension of alcohol 43 (X = Me) (160 mg, 0.47 mmol) in acetonitrile (9 mL). The reaction mixture was heated at 80 C for 5 hours. The reaction mixture was cooled using an ice bath and saturated _{aqueous NaHCO 3} solution was added. The resulting solution was extracted with DCM (3 times). The combined organic phases were washed with brine, dried over MgSO _4. The desired product was obtained by concentrating the solvent. 166 mg, 88% yield, [M + 1] = 403).

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A suspension of the above alkyl bromide derivative (30 mg; 0.075 mmol) in deoxygenated DME (2.7 mL) with a solution of 3-pyridineboronic acid (14 mg, 0.11 mmol) and 2M in Na ₂ CO ₃ ( 0.22 mL, 0.44 mmol) was added. The suspension was stirred at room temperature for 5 minutes, then PdCl ₂ (PPh ₃ ) ₂ (10 mg, 0.015 mmol) was added. The suspension was heated in MW at 85 C for 1 hour. The reaction mixture was cooled, diluted with water and extracted with EtOAc (twice). The combined extracts were washed with brine, dried over MgSO _4. The crude product is obtained by filtration and concentration and purified by two preparative TLCs (eluting system: 3% MeOH in DCM) to give 5.3 mg (18% yield) of product. Compound 111 was obtained. MS: [M + 1] = 401. H ¹ NMR (CDCl ₃ ) δ8.66 (1H, bs), 8.48 (1H, bs), 7.96 (1H, s), 7.79 (1H, s), 7.66 (1H, d, J = 8Hz), 7.50 ( 1H, d, J = 8Hz), 7.43 (1H, d, J = 7Hz), 7.23 (1H, m), 4.42 (2H, q, J = 7Hz), 4.18 (2H, s), 2.54 (3H, s) ), 1.44 (3H, t, J = 7Hz).
Example 22: Synthesis of compound 48:

Scheme 16.

Triethylamine (0.394 mL, 2.82 mmol) and pyridine sulfur trioxide complex (225 mg, 1) in alcohol 43 (186 mg, 0.523 mmol) agitated in DMSO (1 mL) and dichloromethane (2.5 mL) at room temperature. .41 mmol) was added. After stirring for 3 hours, the reaction was quenched with water (5 mL) and extracted 3 times with ethyl acetate. The combined organic solutions were washed with water and brine and dried over י ₄ . Aldehyde product 57 was isolated by ISCO flash column chromatography (RediSep 4g column) using gradient elution of 0.5-8% MeOH in DCM. 84.4 mg (46%) was obtained as a yellowish foamy solid. MS: [M + 1] = 354.

Pyrrolidine (5.5 uL, 0.0658 mmol) was added to a stirred solution of aldehyde 57 (15.5 mg, 0.0439 mmol) in 1,2-dichloroethane (0.3 mL) at room temperature. After stirring for 2 minutes, the solution became clear and NaBH (OAc) ₃ (14.4 mg) was added. The reaction mixture was stirred for 4 hours _{, quenched with saturated NaHCO 3} and extracted 3 times with ethyl acetate. The combined organic layers were washed with water and brine and dried over Na ₂ SO ₄ . Preparative TLC with 10% MeOH in DCM gave 13.1 mg (73%) of the desired compound 48 as a clear film solid. MS: [M + 1] = 409. ¹ H-NMR (500MHz, CDCl3) δ: 7.74 (s, 1H), 7.62 (d, 1H, J = 3.0Hz), 7.51 (d, 1H, J = 9.0Hz), 7.14 (dd, 1H, J = 3.5, 9.0Hz), 4.42 (q, 2H, J = 6.5Hz), 3.94 (s, 3H), 3.87 (br s, 2H), 2.65 (br s, 4H), 1.79 (br s, 4H), 1.44 (t, 3H, J = 7.0Hz).
Example 23: Synthesis of Compound 49:

The compound of Example 23 was obtained as a transparent film-like solid by synthesizing the compound of Example 23 using morpholine in the final step in a synthetic route similar to that described in Example 22. : MS: [M + 1] = 425. ¹ H-NMR (500MHz, CDCl3) δ: 7.75 (s, 1H), 7.63 (d, 1H, J = 3.0Hz), 7.52 (d, 1H, J = 9.5Hz), 7.15 (dd, 1H, J = 3.0, 9.0Hz), 4.42 (q, 2H, J = 7.5Hz), 3.95 (s, 3H), 3.76 (br s, 2H), 3.71 (br s, 4H), 2.57 (br s, 4H), 1.44 (t, 3H, J = 8.0Hz).
Example 24: Synthesis of Compound 50:

The compound of Example 24 was obtained as a transparent film-like solid by synthesizing the compound of Example 24 using diethylamine in the final step in a synthetic route similar to that described in Example 22. : MS: [M + 1] = 411. ¹ H-NMR (500 MHz, CDCl3) δ: 7.74 (s, 1H), 7.64 (br d, 1H, J = 3.0Hz), 7.51 (d, 1H, J = 9.0Hz), 7.15 (dd, 1H, J = 2.5, 9.0Hz), 4.43 (q, 2H, J = 6.5Hz), 3.96 (s, 3H), 3.86 (br s, 2H), 2.64 (br s, 4H), 1.44 (t, 3H, J = 8.5Hz), 1.15 (br s, 6H).
Example 25: Synthesis of Compound 51:

The compound of Example 25 is made into a transparent film-like solid by synthesizing the compound of Example 25 using methylbenzylamine in the final step in a synthetic route similar to that described in Example 22. Obtained: MS: [M + 1] = 459. ¹ H-NMR (500 MHz, CDCl3) δ: 7.75 (s, 1H), 7.63 (d, 1H, J = 3.0Hz), 7.51 (d, 1H, J = 8.5Hz), 7.36 (br d, 2H, J = 8.0Hz), 7.30 (m, 2H), 7.23 (m, 1H), 7.15 (dd, 1H, J = 3.0, 9.0Hz), 4.38 (q, 2H, J = 7.5Hz), 3.95 (s, 3H), 3.85 (br s, 2H), 3.63 (br s, 2H), 2.25 (s, 3H), 1.41 (t, 3H, J = 7.0Hz).
Example 26: Synthesis of Compound 170:

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Isobutyramide oxime (41.8 mg, 0.41 mmol) and ester 48 (27.9 mg, 0.0683 mmol) in a round bottom flask were azeotroped with toluene several times in Rotabap to an anhydrous THF (0.6 mL). It was suspended and then cooled to 0 ° C. NaH (60% oil suspension; 10.9 mg, 0.273 mmol) was added. The ice bath was removed, the reaction mixture was stirred at room temperature for 20 minutes, then heated at 70 ° C. for 6 hours and cooled. Water (4 mL) was added and the mixture was extracted 3 times with EtOAc. The combined organic solutions were washed with brine and dried over י4. Preparative TLC with 10% MeOH in EtOAc gave 10.4 mg (34%) of the desired product, compound 170, as a clear film solid. MS: [M + 1] = 447.
Example 27: Synthesis of Compound 52:

Scheme 17.

The starting alcohol 43 (160 mg, 0.45 mmol) was treated with phosphorus oxybromide (400 mg, 1.4 mmol) in acetonitrile (10 ml) at 80 ° C. for 5 hours. The reaction was then cooled to 0 ° C., quenched with saturated NaHCO3 and extracted twice with dichloromethane. The combined dichloromethane solution was washed with brine, dried over MgSO _4. Filtration and removal of the solvent under reduced pressure gave 173.3 mg (92%) of bromide as a yellowish foam solid. MS: [M + 1] = 418.

_{2M Na 2} CO ₃ (0.39 ml, 0.78 mmol) and 3-chlorophenylboronic acid (42.) In suspension of bromide (55 mg, 0.131 mmol) in dimethoxyethane (2 ml; degassed). 2 mg, 0.27 mmol) was added. The reaction mixture was stirred at room temperature for 2 minutes, then Pd (PPh ₃ ) ₄ (75 mg, 0.065 mmol) was added and the suspension was heated in an oil bath at 85 ° C. for 90 minutes. Once cooled, the reaction mixture was diluted with EtOAc and washed with brine. The aqueous layer was separated and extracted 3 times with EtOAc. All organic layers were pooled _{, dried over Na 2} SO ₄ , then filtered and the solvent removed under reduced pressure. The product was isolated by continuous preparative TLC purification using 20% hexane in EtOAc followed by 5% MeOH in DCM. 9.6 mg of product (Compound 52) was obtained as a brownish solid. MS: [M + 1] = 450. ¹ H-NMR (500 MHz, CDCl3) δ: 7.75 (s, 1H), 7.64 (d, 1H, J = 3.0Hz), 7.51 (d, 1H, J = 9.5Hz), 7.31 (br s, 1H) , 7.23 (br s, 1H), 7.17 (m, 3H), 4.43 (q, 2H, J = 7.0Hz), 4.15 (s, 2H), 3.96 (s, 3H), 1.44 (t, 3H, J = 8.0Hz).
Example 28: Synthesis of Compound 53:

The compound of Example 28 was browned by synthesizing the compound of Example 28 using 3-cyanophenylboronic acid in the last step in a synthetic route similar to that described in Example 27. Obtained as a solid: MS: [M + 1] = 441. ¹ H-NMR (500 MHz, CDCl3) δ: 7.75 (s, 1H), 7.66 (br s, 1H), 7.64 (d, 1H, J = 3.0Hz), 7.61 (br d, 1H, J = 7.5Hz) ), 7.39 (t, 1H, J = 7.5Hz), 7.16 (dd, 1H, J = 3.5, 9.5Hz), 4.45 (q, 2H, J = 7.0H), 4.20 (s, 2H), 3.96 (s) , 3H), 1.45 (t, 3H, J = 7.0Hz).
Example 29: Synthesis of Compound 54:

In a similar synthetic route as that described in Example 27, starting from the alcohol is R 1 ₌ methyl, using 2-chlorophenylboronic acid in the last step, by synthesizing the compound of Example 29 , The compound of Example 29 was obtained as a brownish solid: MS: [M + 1] = 434.
Example 30: Synthesis of Compound 101:

In a similar synthetic route as that described in Example 27, starting from the alcohol is R 1 ₌ methyl, using phenylboronic acid in the last step, by synthesizing the compound of Example 30, carried out The compound of Example 30 is obtained as a brownish solid product, which is chromatographed (RediSep 4g silica-gel column. Elution solvent: EtOAc) followed by preparative TLC (elution system: 40% DCM / 40% hexane / 17% EtOAc). Purification with / 3% MeOH) gave compound 101, which is a product of 5.9 mg (31% yield). MS: [M + 1] = 402. H ¹ NMR (CDCl ₃ ) δ7.96 (1H, s), 7.77 (1H, s), 7.55 (1H, m), 7.47 (1H, m), 7.32 (5H, m), 4.41 (2H, q, J = 7Hz), 4.17 (2H, s), 2.53 (3H, s), 1.43 (3H, t, J = 7Hz).
Example 31: Synthesis of Compound 102:

Activated 10% Pd / C (5 mg) was added to the suspension of the bromide in EtOAc (2 mL) and MeOH (2 mL). The suspension was stirred under a hydrogen atmosphere for 48 hours. The solution was filtered through Celite. The filtrate was concentrated and purified by chromatography (RediSep 4g silica-gel column. Elution solvent: EtOAc) to give 15.9 mg (33%) of the desired product compound 102. MS: [M + 1] = 324. H ¹ NMR (CDCl ₃ ) δ7.96 (1H, s), 7.78 (1H, s), 7.49 (1H, d, J = 9Hz), 7.42 (1H, d, J = 8Hz), 4.43 (2H, q) , J = 7.5Hz), 2.53 (3H, s), 2.44 (3H, s), 1.45 (3H, t, J = 7.5Hz).
Example 32: Synthesis of compound 108:

スキーム１８ｂ．

実施例３３：化合物５５の合成：

2-Chlorophenylboronic acid (10 mg, 0.065 mmol) and 2 M Na _{2 in a suspension of the bromide derivative (18 mg; 0.043 mmol) with R 1} = OME in deoxygenated DME (2 mL). A CO ₃ solution (0.13 mL, 0.26 mmol) was added. The suspension was stirred at room temperature for 15 minutes, then PdCl ₂ dppf (7 mg, 0.009 mmol) was added. The suspension was heated in an 85C oil bath for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc (twice). The combined extracts were washed with brine and dried over Na ₂ SO ₄ . The crude product is obtained by filtration and concentration and purified by preparative TLC (eluting system: 5% MeOH / 47.5% Hex / 47.5% EtOAc) to 3.5 mg (18% yield). ) Was obtained. MS: [M + 1] = 451. H ¹ NMR (CDCl ₃ ) δ7.77 (1H, s), 7.63 (1H, d, J = 3Hz), 7.52 (1H, d, J = 11.5Hz), 7.36 (1H, m), 7.31 (1H, m), 7.18 (2H, m), 7.14 (1H, dd, J = 3, 9Hz), 4.38 (2H, q, J = 7Hz), 4.27 (2H, s), 3.94 (3H, s), 1.41 ( 3H, t, J = 7Hz).
Scheme 18a.

Scheme 18b.

Example 33: Synthesis of compound 55:

DIPEA (8.65 g, 67 mmol), HOBt (5.4 g, 36.85 mmol) and EDCI (9.6 g, 50.3 mmol) in a solution of compound 58 (6.6 g, 33.5 mmol) in dichloromethane (100 mL). ) Was added. After stirring for about 15 minutes, a solution of 2,4-dimethoxybenzylamine (5.6 g, 33.5 mmol) in dichloromethane (50 mL) was added dropwise to the uniform reaction mixture in a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction mixture was washed successively with 1N NaOH (100 mL), water (100 mL) and brine (100 mL). The organic phase was then _{dried over Na 2} SO ₄ and evaporated to give the crude solid product 59, which was crystallized from ethyl ether. Filtration and open air suction drying gave 9.8 g (96%) of pure off-white solid product (MS: [M + 1] = 347).

10% wet Pd-C (1.8 g, 10% mmol) was added to a solution of compound 59 (9.8 g, 28.3 mmol) in MeOH / EtOAc (1: 1,100 mL). After three consecutive exhausts and flushing of nitrogen, the heterogeneous reaction mixture was subjected to balloon hydrogenation at atmospheric pressure for about 4 hours until hydrogen absorption stopped. The reaction mixture was filtered through a Celite pad and evaporated to give the pure desired product 60 as a brown oil. 8.63 g (96%) (MS: [M + 1 = 317]). This product was used as is in the next step.

Triethylamine (5.5 g, 54.6 mmol) was added to a solution of compound 60 (8.63 g, 27.3 mmol) in dichloromethane (100 mL). The mixture was cooled using an ice bath and treated with bromoacetyl chloride (5.2 g, 32.76 mmol) under a nitrogen atmosphere. The ice bath was removed and the mixture was left agitated for 18 hours. The reaction mixture _{was washed successively with saturated NaHCO 3} (100 mL), water (100 mL) and brine (100 mL). The organic phase was then _{dried over Na 2} SO ₄ and evaporated to give the crude solid product 61. The crude product was crystallized from methanol, filtered and dried to give 10.3 g (87%) of pure brown solid product [MS: 439].

Solution _{K 2 CO 3 (4.8g, 45.8mmol} ) of compound 61 in DMF (1000mL) (10g, 22.9mmol ) was added. The mixture was heated at 50 ° C. for 24 hours. LCMS showed complete conversion to the desired product. The mixture was cooled to room temperature and the inorganic solid was filtered. The solvent was removed under high vacuum. The resulting crude product 62 was crystallized from methanol, filtered and dried to give 6.4 g (78%) of pure brown solid product (MS: [M + 1] = 357).

T-BuOK (97%, 1.88 g, 16.28 mmol) was added to compound 62 (4.46 g, 12.52 mmol) dissolved in 2.5: 1 THF / DMF (50 mL) at −20 ° C. The mixture was heated to 25 ° C., stirred for 30 minutes and then cooled to −20 ° C. again. After diethyl chlorophosphate (2.35 mL, 16.28 mmol) was added dropwise, the mixture was stirred for 3 hours while heating from −20 ° C. to 25 ° C. The reaction mixture was recooled to 0 ° C. and ethyl isocyanoacetate (1.92 mL, 17.53 mmol) was added thereto. Then, after cooling to −78 ° C., t-BuOK (97%, 1.88 g, 16.28 mmol) was added, and the mixture was stirred at room temperature for 5 hours. Progress was monitored by LC / MS. 4.81 g by quenching the reaction by adding 1: 1 saturated NaHCO ₃ / H ₂ O (140 mL), filtering the precipitate _{, washing with H 2} O and air drying overnight. (85%) of the imidazole derivative 63 was obtained as a yellow solid (MS: [M + 1] = 452).

Trifluoroacetic acid (35 mL) was added to compound 63 (4.81 g, 10.65 mmol) in dichloromethane (35 mL) at 0 ° C., and then trifluoromethanesulfonic acid (1.9 mL, 21.31 mmol) was added dropwise. did. The mixture was warmed to room temperature, stirred for 2 hours and then concentrated to give a residue, which was dissolved in dichloromethane (120 mL). The crude solution was divided into _{cooled saturated NaHCO 3 and dichloromethane.} The organic extracts were combined, dried (MgSO _4), filtered and concentrated to give a sufficient deprotected product purity 3.2g (99%) 64 (brown solid), the next step (MS: [M + 1] = 302).

_{POCl 3} (52.) To lactam 64 (51.8 mg, 0.172 mmol) and N, N-dimethyl-p-toluidine (93.0 mg, 0.688 mmol) stirred in chlorobenzene (1 ml) under nitrogen. 7 mg, 0.344 mmol) was added. The reaction was then heated at 135 ° C. for 2 hours. After cooling to room temperature, phenoxyacetic acid hydrazide (228.4 mg, 1.36 mmol) was added in situ to imino-chloride 65, followed by DIPEA (90 ul). The reaction was stirred at room temperature for 30 minutes and then heated at 100 ° C. for 90 minutes. The reaction mixture was cooled, saturated NaHCO ₃ (aqueous solution) was added and extracted 3 times with ethyl acetate; the combined organic layers were washed with brine and dried over י ₄ . After filtration and concentration, the product as compound 55 was isolated as a white solid by ISCO flash column chromatography (RediSep 4g column, 1-10% MeOH in DCM as elution gradient). Wt: 8.6 mg. MS: [M + 1] = 432. ¹ H-NMR (500 MHz, CDCl3) δ: 7.81 (s, 1H), 7.71 (d, 1H, J = 3.5Hz), 7.52 (d, 1H, J = 9.0Hz), 7.32 (m, 2H), 7.21 (dd, 1H, J = 2.5, 8.5Hz), 7.11 (d, 2H, J = 8.5Hz), 7.02 (m, 1H), 5.44 (s, 2H), 4.38 (q, 2H, J = 7.5Hz) ), 3.94 (s, 3H), 1.39 (t, 3H, J = 7.0Hz).
Example 34: Synthesis of compound 56:

The compound of Example 34 is yellowish by synthesizing the compound of Example 34 using 4-fluoro-phenoxyacetic acid hydrazide in the last step in a synthetic route similar to that described in Example 33. Obtained as a solid: MS: [M + 1] = 450. ¹ H-NMR (500 MHz, CDCl3) δ: 7.82 (s, 1H), 7.73 (d, 1H, J = 3.5Hz), 7.53 (d, 1H, J = 10.0Hz), 7.22 (dd, 1H, J = 3.5, 9.0Hz), 7.08-6.99 (m, 4H), 5.41 (s, 2H), 4.41 (q, 2H, J = 7.0Hz), 3.95 (s, 3H), 1.42 (t, 3H, J = 6.5Hz).
Example 35: Synthesis of Compound 103:

In a synthetic route similar to that described in Example 33, the compound of Example 35 was made a yellowish solid by synthesizing the compound of Example 35 using 2-methoxyacetic acid hydrazide in the last step. Obtained as: MS: [M + 1] = 370.
Example 36: Synthesis of Compound 118:

Acetamide oxime (8.4 mg, 0.108 mmol) was azeotroped with toluene three times in Rotabap and then suspended in THF (1.0 mL). NaH (60% mineral suspension; 3.3 mg, 0.081 mmol) was added and the mixture was stirred at room temperature for 10 minutes. Next, ester 55 (23.2 mg, 0.054 mmol) was added. After stirring at room temperature for 40 minutes, the reaction mixture was heated at 70 ° C. for 4 hours. Once cooled, cold water (5 mL) is added to the reaction mixture, the precipitate is collected by filtration, washed with water and dried to give 9.7 mg (41%) of the desired product a yellowish solid. Got as. MS: [M + 1] = 442.
Example 37: Synthesis of compound 128:

In a synthetic route similar to that described in Example 36 above, the compound of Example 37 is made into a brownish solid by synthesizing the compound of Example 37 using the ester compound 103 in the final step. Obtained: MS: [M + 1] = 380.
Example 38: Synthesis of Compound 130:

The compound of Example 38 was yellowish by synthesizing the compound of Example 38 by starting from the ester compound 103 and condensing with isobutyramide oxime in a synthetic route similar to that described in Example 36. Obtained as a solid: MS: [M + 1] = 408.
Example 39: Synthesis of Compound 119:

Neopentyl alcohol (30.4 mg, 0) to the above carboxylic acid (13.9 mg, 0.0345 mmol; obtained by LiOH hydrolysis of precursor ester 55) stirred in DCM (0.2 mL). .345 mmol), DMAP (4.2 mg, 0.0345 mmol) and EDC (20 mg, 0.104 mmol) were added. After stirring for 5 hours, the reaction mixture was diluted with EtOAc _{, washed with saturated NH 4} Cl, saturated NaHCO ₃ and brine, and dried over 00544. Silica gel chromatographic purification with a gradient of 0-8% MeOH in EtOAc gave 11.7 mg (72%) of the desired product, compound 119, as a yellowish solid. MS: [M + 1] = 474.
Example 40: Synthesis of compound 120:

By synthesizing the compound of Example 40 using 2-propyl alcohol in the final step in a synthetic route similar to that described in Example 39 above, the compound of Example 40 is a yellowish solid. Obtained as: MS: [M + 1] = 446.
Example 41: Synthesis of Compound 129:

By treating compound 103 (scheme 18a) (66.1 mg, 0.179 mmol) with LiOH (21.4 mg, 0.895 mmol) for 2 hours at room temperature, THF / water / MeOH (total 1.8 ml, 6). Hydrolyzed in a solvent system (ratio of 5/1). The reaction mixture was acidified by adding dilute HCl (pH about 3). The precipitate was collected by filtration, washed with water and dried to give 49.0 mg (80%) of acid as a brownish solid.

The acid thus obtained was stirred in DMF (0.7 mL) at 0 ° C. After adding NaHCO ₃ (48.1 mg, 0.572 mmol), N-bromosuccinamide (96.7 mg, 0.543 mmol) was added. After stirring overnight, the reaction was diluted with EtOAc and washed with _{saturated NaHCO 3.} The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over regsvr4, filtered and concentrated. The bromide of the product was obtained as a white solid by silica gel column chromatography using gradient elution of 0-13% MeOH in EtOAc (Compound 129). Wt: 28.6 mg (53%). MS: [M + 1] = 377.
Example 42: Synthesis of Compound 131:

Compound 129 (22.6 mg, 0.060 mmol) was hydrogenated with 10% Pd-C in EtOAc (1 mL) and MeOH (1 mL) for 16 hours. Filtration with Celite and removal of the solvent gave 14.9 mg (84%) of the des-bromo product, Compound 131, as a slightly yellowish solid. MS: [M + 1] = 298.
Example 43: Synthesis of Compound 122:

A phenoxy analog of acid 66 (scheme 18a R ₁ = OPh) (20.4 mg, 0.0506 mmol) was suspended in DCM (0.5 mL) at room temperature and stirred. Carbonyldiimidazole (16.4 mg, 0.101 mmol) was added. After stirring for 2 hours, the resulting suspension was cooled to 0 ° C. and ammonia (30 uL) was added dropwise. After stirring for 20 minutes, the ice bath was removed and the reaction was allowed to proceed at room temperature for 1 hour. The reaction was concentrated by removing the DCM under reduced pressure. Water (3 mL) was added, the precipitate was collected by filtration, washed with water and dried to give 16.2 mg of crude primary amide, which was used without further purification.

The primary amide (16.2 mg, 0.0402 mmol) was _{treated overnight with POCl 3} (46.2 mg, 0.302 mmol) in 1,4-dioxane (0.5 mL) at 95 ° C. The reaction mixture was then _{quenched with saturated NaHCO 3} (5 mL), cooled to 0 ° C., and the precipitate was collected by suction filtration, washed with water and dried to give 13.6 mg (88%) of nitrile. Was obtained as a brownish solid to give compound 122. MS: [M + 1] = 385.
Example 44: Synthesis of Compound 123:

Acid 66 (15.8 mg, 0.0392 mmol) agitated in THF (0.15 mL) and DCM (0.15 ml), N, O-dimethylhydroxylamine HCl (4.6 mg, 0.047 mmol) and N-hydroxylbenzotriazole hydrate (6.0 mg) was added. EDC (11.3 mg, 0.0588 mmol) and triethylamine (11.9 mg, 0.118 mmol) were then added, the reaction was stirred at room temperature for 12 hours, diluted with EtOAc and saturated with NH ₄ Cl, brine. It was washed and dried with י ₄ . Filtration was performed to remove the solvent under reduced pressure to give 14.4 mg (82%) Weinreb amide, which was used without further purification.

Ethylmagnesium bromide etherate (3M; 0.323 mL) was added to Weinreb amide (14.4 mg, 0.0323 mmol) stirring in THF (0.3 mL) at 0 ° C. The reaction was warmed to room temperature and stirred for 14 h, quenched with saturated _NH 4 Cl, extracted 3 times with EtOAc; the combined organic layers were washed with brine, dried over MgSO _4. Filtration was performed to remove the solvent to give the crude ketone product, which was purified by preparative TLC using 8% MeOH in EtOAc. Wt: 4.6 mg (34%) of compound 123. MS: [M + 1] = 416.
Example 45: Synthesis of Compound 124:

The Weinreb amide (18.0 mg, 0.0403 mmol) described above was treated with DIBAL (1 M THF; 0.363 mL) at −78 ° C. for 1 hour and then still at −78 ° C. in a Rochelle salt solution (1M THF; 0.363 mL). 20%) overnight. The aqueous solution was extracted 3 times with EtOAc; the combined organic layers were washed with brine, dried over MgSO _4. Filtration and removal of the solvent under reduced pressure gave 13.7 mg of crude aldehyde, which was used without further purification.

Crude aldehyde (13.7 mg) in DCM (0.7 mL) at room temperature was treated with Deoxo-Fluor (54.8 mg, 0.248 mmol) for 16 hours. The reaction was quenched 20 minutes with saturated NaHCO ₃ (5 mL), and extracted 3 times with EtOAc; the combined organic layers were washed with brine, dried over MgSO _4. After filtration to remove the solvent, preparative TLC purification using 10% MeOH in EtOAc gave 7.5 mg (52%) of the desired difluoride compound 124 as a yellowish solid. MS: [M + 1] = 410.
Example 46: Synthesis of Compound 142:

実施例４７：化合物１０６の合成：

Weinreb amide (8.8 mg, 0.0197 mmol) from the above in THF (0.15 mL) at 0 ° C. was treated with phenylmagnesium bromide (1 M THF; 0.54 mL) for 2.5 hours and saturated NH ₄ Cl. in quenched, extracted twice with EtOAc; the combined organic layers were washed with brine, dried over MgSO _4. Crude ketones were obtained by filtration to remove the solvent and used without further purification. The ketone in THF (0.5 mL) was _{treated with NaBH 4} (6 mg) at _{room temperature for 2 hours, then quenched with saturated NH 4} Cl and extracted 3 times with EtOAc; the combined organic layers were washed with brine. , Chloride ₄ dried. Crude alcohol was obtained by filtering to remove the solvent and used without further purification. The alcohol (1.4 mL) in the DCM thus obtained was treated with triethylsilane (86.4 mg, 0.75 mmol) and trifluoroacetic acid (171.0 mg, 1.5 mmol) overnight at 40 ° C. Then concentrated under reduced pressure, diluted with EtOAc _{, washed with saturated NaHCO 3} and brine, and dried with regsvr ₄ . By filtering to remove the solvent, a crude benzyl product was obtained and purified by silica gel column chromatography using 0-12% MeOH in EtOAc as an eluent; 3.6 mg of compound 142. Obtained as a yellowish solid. MS: [M + 1] = 450.
Scheme 19:

Example 47: Synthesis of Compound 106:

Lactam 64 (185.7 mg, 0.616 mmol) in chlorobenzene (5 mL), N, N-dimethyl-p-toluidine (333.3 mg, 2.465 mmol) and phosphorus oxychloride (188.9 mg, 1.232 mmol). Was added. The reaction mixture was heated at 135 ° C. for 2 hours, cooled to room temperature, formylation hydrazide (296.0 mg, 4.93 mmol) was added, and then diisopropylethylamine (238.8 mg, 1.85 mmol) was added. After stirring at room temperature for 30 minutes, the reaction is heated at 100 ° C. for 1 hour, cooled, saturated NaHCO ₃ (15 mL) is added and extracted twice with EtOAc; the combined organic layers are washed with brine. It was dried with 00544. Crude triazole product is obtained by filtration to remove the solvent and is purified by silica gel column chromatography with 0-15% MeOH elution in EtOAc to give 35.9 mg (18%). Obtained as a brownish solid. MS: [M + 1] = 326.

The triazole from above in DCM (1 mL) was treated with N-bromosuccinamide (37.6 mg, 0.21 mmol) at 0 ° C. The reaction was slowly warmed to room temperature, the reaction proceeds at room temperature overnight, diluted with EtOAc, washed with saturated NaHCO _3, brine, dried over MgSO _4. Filtration was performed to remove the solvent to give a crude bromide, which was purified by silica gel column chromatography using a MeOH gradient of 0-10% in EtOAc; 22.9 mg (51%) of compound 106 off. Obtained as a white solid. [MS]: 406.
Example 48: Synthesis of compound 104:

In a microwave reaction vessel, phenol (20.3 mg, 0.216 mmol), bromide substrate from Example 47 (29.1 mg, 0.0719 mmol), Cs ₂ CO ₃ (117.0 mg, 0.360 mmol), 1, Diethyl 3-acetonedicarboxylic acid (14.5 mg, 0.0719 mmol) and DMF (0.5 ml) were added. Nitrogen gas was flowed through the container. CuI (6.8 mg, 0.036 mmol) was added and the mixture was stirred at room temperature for 5 minutes and then heated at 140 ° C. for 60 minutes under MW irradiation conditions. The reaction mixture was diluted with EtOAc, washed with water; the aqueous layer was separated, extracted twice with EtOAc; the combined organic solution was washed with brine, dried over MgSO _4. Filtration to remove the solvent gave the crude ether product, which was purified by preparative TLC with 5% MeOH in DCM; 6.6 mg of compound 104 was obtained as a yellowish solid. .. MS: [M + 1] = 418.
Example 49: Synthesis of compound 105:

実施例５０：化合物１１２の合成：

A yellowish foam of the compound of Example 49 by synthesizing the compound of Example 49 using 3-methoxyphenol instead of phenol in a synthetic route similar to that described in Example 48 above. Obtained as a state solid: MS: [M + 1] = 448.
Scheme 20:

Example 50: Synthesis of Compound 112:

LiOH (59 mg, 2.45 mmol) was added to a solution of compound 2 (160 mg, 0.49 mmol) in THF (6 mL), water (5 mL) and MeOH (1 mL). The solution was stirred at room temperature for 3 hours. The solution was concentrated and the crude material was acidified to pH 3-4 with 1N HCl. No solid was observed. EtOAc was added and the organic phase was extracted (3 times). The combined extracts were washed with brine, dried over MgSO _4. Filtration and concentration gave 112 mg (77% yield) of the desired carboxylic acid product as an orange solid. MS: [M + 1] = 300.

Thionyl chloride (0.4 mL; 5 mmol) and DMF (20 μL) were added to the suspension of acid (30 mg, 0.1 mmol) in dichloroethane (0.2 mL). The resulting solution was heated at 70 C for 1 hour. An additional 0.2 mL of thionyl chloride was added and the solution was heated for an additional 30 minutes. The solvent was removed. The crude material was dried under reduced pressure.

The crude acid chloride (0.1 mmol) was suspended in isopropanol and stirred at room temperature for 18 hours. The solvent was evaporated and the crude material was purified by chromatography (RediSep 4g silica-gel column, eluted with 10% MeOH in DCM) to give compound 112 as a product of 8.6 mg (25% yield). .. [M + 1] = 342). H ¹ NMR (CDCl ₃ ) δ7.90 (1H, d, J = 9Hz), 7.79 (1H, bs), 7.63 (1H, bs), 7.36 (1H, bs), 3.48 (1H, m), 2.45 ( 3H, s), 1.43 (6H, d, J = 6.5Hz).
Example 51: Synthesis of Compound 113:

The crude acid chloride (0.066 mmol) prepared above was suspended in dichloroethane (1 mL), and 2,2-dimethyl-1-propanol (300 mg, 3.4 mmol) was added. The solution was stirred at room temperature for 18 hours. No product was formed. DMAP (5 mg, 0.004 mmol) and DCC (15 mg, 0.073 mmol) were added to the above solution. The solution was stirred at room temperature for 2 hours. The reaction mixture was applied as is to a preparative TLC (elution system: 75 EtOAc in hexanes) to give 7.2 mg (30% yield) of compound 113. MS: [M + 1] = 370. H ¹ NMR (CDCl ₃ ) δ7.91 (1H, dd, J = 3, 9Hz), 7.79 (1H, s), 7.61 (1H, dd, J = 4.5, 9Hz), 7.35 (1H, m), 4.11 (2H, s), 2.44 (3H, s), 1.07 (9H, s).
Example 52: Synthesis of compound 114:

The crude acid chloride (0.066 mmol) prepared above was suspended in dichloroethane (1 mL) and 2,2,2-trifluoroethanol (0.1 mL, 1.4 mmol), and then triethylamine (0.6 mL). , 4.3 mmol) was added. The solution was stirred at room temperature for 2 hours and 30 minutes. The solvent is evaporated and the crude material is purified by chromatography (RediSep 4g silica-gel column, eluted with EtOAc) and then by preparative TLC (eluting system: 70% EtOAc in hexanes) at 8.1 mg (. Compound 114, which is the product (32% yield), was obtained. [M + 1] = 382). H ¹ NMR (CDCl ₃ ) δ7.91 (1H, dd, J = 3.5, 9.5Hz), 7.83 (1H, s), 7.63 (1H, dd, J = 4.5, 9.5Hz), 7.35 (1H, m) , 4.77 (2H, m), 2.43 (3H, s).
Example 53: Synthesis of Compound 136:

_{NaHCO 3} (111 mg, 1.32 mmol) was added to the solution of acid (100 mg, 0.33 mmol) prepared in Example 50 in DMF (1.5 mL) cooled using an ice bath, and then NBS. (117 mg, 0.66 mmol) was added. The solution was stirred at room temperature for 14 hours. The reaction mixture was diluted with water and extracted with EtOAc (5 times). The combined extracts were washed with brine (twice) and dried with _ו4. Crude products were obtained by filtration and concentration. Chromatography (RediSep 4g silica-gel column, eluted with EtOAc) gave compound 136, a product of 93 mg (85% yield) [M + 1] = 334). H ¹ NMR (CDCl ₃ ) δ7.87 (1H, dd, J = 2.5, 8.5Hz), 7.72 (1H, s), 7.56 (1H, dd, J = 6, 10Hz), 7.33 (1H, m), 2.44 (3H, s).
Example 54 Synthesis of Compound 139:

General coupling procedure: Phenylboronic acid (11 mg, 0.092 mmol), carbonate in a solution of compound 136 (20 mg, 0.061 mmol) in degassed DME (0.9 mL) and water (0.1 mL). Cesium (80 mg, 0.24 mmol) and PdCl ₂ dppf (5 mg, 0.066 mmol) were added. The suspension was heated at 80 ° C. for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc (3 times). The combined extracts were washed with brine (twice) and dried in י ₄ . Filtration and concentration gave the crude product, which was purified by preparative TLC (eluting system: 3% MeOH in EtOAc).

Compound 139 was prepared with phenylboronic acid. 10.8 mg (54% yield) of product was obtained. MS: [M + 1] = 332. H ¹ NMR (CDCl ₃ ) δ7.87 (1H, dd, J = 3.5, 9.5Hz), 7.85 (1H, s), 7.63 (3H, m), 7.50 (2H, t, J = 6.5Hz), 7.35 (2H, m), 2.41 (3H, s).
Example 55: Synthesis of Compound 140:

Compound 140 was prepared in the same manner using 3-pyridineboronic acid. 8.9 mg (27% yield) of product was obtained. MS: [M + 1] = 333. H ¹ NMR (CDCl ₃ ) δ8.86 (1H, s), 8.63 (1H, d, J = 5Hz), 8.01 (1H, m), 7.90 (2H, m), 7.64 (1H, dd, J = 5.5) , 9Hz), 7.44 (1H, m), 7.36 (1H, m), 2.39 (3H, s).
Example 56: Synthesis of Compound 152:

Compound 152 was prepared using 1-methylpyrazole-4-boronic acid, HCl. 12.5 mg (63% yield) of product was obtained. MS: [M + 1] = 336. H ¹ NMR (CDCl ₃ + MeOD ₄ ) δ9.04 (1H, bs), 7.99 (1H, bs), 7.75 (2H, m), 7.41 (2H, m), 3.95 (3H, s), 2.32 (3H) , s).
Example 57: Synthesis of compound 154:

実施例５８：化合物１１７の合成：

Compound 154 was prepared using 2-methylpyridine-4-boronic acid pinacol ester. 7.1 mg (34% yield) of product was obtained. MS: [M + 1] = 347. H ¹ NMR (CDCl ₃ ) δ8.6 (1H, d, J = 6Hz), 7.89 (1H, dd, J = 3.5, 8.5Hz), 7.87 (1H, s), 7.64 (1H, dd, J = 5.5) , 9Hz), 7.48 (1H, s), 7.36 (2H, m), 2.64 (3H, s), 2.41 (3H, s).
Scheme 21:

Example 58: Synthesis of Compound 117:

In a 100 mL round bottom flask, lactam ester 16'(2 g, 7.35 mmol; prepared in a format similar to 16 described in Scheme 11) was dissolved in 60 mL anhydrous THF. The solution was stirred at room temperature under a nitrogen atmosphere. LiBH ₄ (2M in THF, 4 mL, 8 mmol) was added slowly. The reaction mixture was stirred under a nitrogen atmosphere for 18 hours. Further LiBH ₄ (2M in THF, 2 mL, 4 mmol) was added slowly. The reaction mixture was stirred for an additional 24 hours. A mixture of EtOAc / EtOH (20 mL / 20 mL) was added to the reaction mixture and concentrated. The residue was dissolved in MeOH and silica gel was added. After evaporating the volatile solvent, the solid was loaded into a RediSep 40g silica-gel column. The desired product was eluted with 5: 1 v / v CH ₂ Cl _{2 / MeOH.} Alcohol was obtained as a white solid (1.14 g, 67% yield). MS: [M + 1] = 231.

The alcohol (1.14 g, 4.96 mmol) was suspended in 16 mL of AcOH at 33% HBr and heated at 80 ° C. for 18 hours. The solution was cooled using an ice bath and diluted with EtOAc. A white solid could be observed. Saturated NaHCO ₃ aqueous solution was added slowly. Solids were solubilized with large amounts of EtOAc and MeOH. Extracting the organic phase (3 times), the combined organic phases were washed with brine, dried over MgSO _4. The crude product was obtained by filtration and concentration and used in the next step without further purification. MS: [M + 1] = 293.

To a solution of the alkyl bromide derivative (4.96 mmol) in EtOAc (50 mL), MeOH (200 mL) and THF (50 mL) was added wet 10% Pd / C (250 mg) and the resulting suspension was hydrogenated. It was stirred under 7 days. The suspension was filtered through Celite, the resulting solution was concentrated and co-evaporated with toluene. The crude product was used in the next step without further purification.

_{I-Pr 2} NEt (7.6 mL, 43.6 mmol) was added to a solution of 1,2,4-triazole (2.7 g, 39.7 mmol) in _{anhydrous CH 3} CN (20 mL) at 0 ° C. Once all triazoles were dissolved, POCl ₃ (1.11 mL, 11.9 mmol) was added. The mixture was stirred at 0 ° C. for 2 hours. The solution was transferred to a flask containing lactam (4.96 mmol). The resulting solution was heated in an oil bath at 80 ° C. for 16 hours. The viscous mixture was cooled using an ice bath to evaporate the solvent. Dilute with EtOAc and add water. It was extracted 5 times with EtOAc. The combined extracts were washed with brine, dried over MgSO _4. The crude product was obtained by filtration and concentration and used as is in the next reaction. MS: [M + 1] = 266.

A solution of KOtBu (1.11 g, 9.92 mmol) in DMF (10 mL) was cooled to −50 ° C. under a nitrogen atmosphere. Ethyl acetate (1.2 mL, 10.9 mmol) was added slowly. The mixture was stirred at −60 ° C. to −40 ° C. for 1 hour. The crude 1,2,4-triazolo intermediate (4.96 mmol) from step 4 in DMF (5 mL) was slowly added. The mixture was warmed to room temperature for 16 hours. The addition of saturated aqueous _NH 4 Cl and it was extracted 3 times with EtOAc. The combined extracts were washed with brine (3 times) and dried with _ו4. Crude products were obtained by filtration and concentration. Chromatography (RediSep 24 g silica-gel column, eluted with 70% EtOAc in hexanes) gave 296 mg (20% yield for 4 steps) of product. MS: [M + 1] = 310.

LiOH (117 mg, 4.85 mmol) was added to a solution of the ester derivative (260 mg, 0.84 mmol) in THF (6 mL), water (5 mL) and MeOH (1 mL). The solution was stirred at room temperature for 3 hours. The solution was concentrated and the crude material was acidified to pH 3-4 with 1N HCl. The solid was recovered by multiple filtrations to give 178 mg (75% yield) of the desired product. MS: [M + 1] = 282.

CDI (50 mg, 0.31 mmol) was added to the suspension of acid (80 mg, 0.28 mmol) in THF (2 mL). The suspension was heated at 65 ° C. for 3 hours. LCMS showed that the reaction was incomplete. Additional CDI (10 mg) was added and the solution was heated for an additional hour. The solution was cooled to room temperature and NH ₄ OH solution (1 mL) was added. The solution was stirred for 1 hour. The solid was recovered by filtration to give 33 mg (42%) of compound 117 as the desired product as a white solid. MS: [M + 1] = 281. H ¹ NMR (MeOD ₄ ) δ8.1 (1H, s), 7.9 (1H, s), 7.73 (3H, m), 7.07 (2H, s), 2.40 (3H, s).
Example 59: Synthesis of compound 115:

Trifluoroacetic anhydride (8 μL; 0.058 mmol) was added to a suspension of compound 117 (8 mg, 0.029 mmol) and triethylamine (8 μL; 0.058 mmol) in THF (1 mL). The reaction mixture was stirred at room temperature for 16 hours. LCMS showed only 30% conversion. Further trifluoroacetic anhydride (30 μL) and triethylamine (30 μL) were added. The solution became clear and stirred for an additional hour. The reaction was quenched with MeOH. The solvent was evaporated and the crude material was purified by preparative TLC (eluting system: 70% EtOAc in hexanes) to give 6.6 mg (83%) of compound 115. MS: [M + 1] = 263. H ¹ NMR (CDCl ₃ ) δ8.17 (1H, d, J = 7Hz), 7.88 (1H, s), 7.67 (3H, m), 2.46 (3H, s).
Example 60: Synthesis of Compound 127:

Hydroxylammonium hydrochloride (6 mg, 0.09 mmol) and potassium carbonate (12 mg, 0.09 mmol) in a suspension of compound 115 (16 mg, 0.06 mmol) in EtOH (0.8 mL) and water (0.2 mL). Was added. The suspension was heated at 80 ° C. for 16 hours. The solution was diluted with EtOAc and washed with water. The aqueous layer was separated and extracted with EtOAc (3 times). The combined organic phases were washed with brine, dried over MgSO _4. Filtration and concentration gave 12.2 mg (67% yield) of the desired product. MS: [M + 1] = 296.

A suspension of oxime (10 mg, 0.034 mmol) in acetic anhydride (0.5 mL) was heated at 110 C for 1 hour. The solution was then heated at 130 C for 1 hour. Finally, the temperature was raised to 140 ° C. and heated for another 2 hours. The reaction mixture was cooled, EtOH (1 mL) was added to the reaction mixture and it was heated at 80 ° C. for 16 hours. The solvent was evaporated and the crude material was purified by preparative TLC (eluting system: EtOAc) to give 6.1 mg (56% yield) of the desired product, compound 127. MS: [M + 1] = 320). H ¹ NMR (CDCl ₃ ) δ8.16 (1H, m), 7.92 (1H, s), 7.65 (3H, m), 2.68 (3H, s), 2.46 (3H, s).
Example 61: Synthesis of Compound 133:

CDI (10 mg, 0.062 mmol) was added to a solution of isobutyric acid (19 μL, 0.2 mmol) in THF (0.5 mL). The solution was stirred at room temperature for 2 hours. The solution was then transferred to a vial containing the oxime derivative (12 mg, 0.041 mmol) described above and heated at 70 ° C. for 2 hours. LCMS showed that the reaction was incomplete. Another batch of reagents (isobutyric acid and CDI) was prepared, added to the reaction mixture and heated at 70 ° C. for an additional hour. LCMS showed that all starting materials were consumed. The solvent was evaporated, the crude material was suspended in isobutyric acid (1 mL) and heated at 130 ° C. for 1 hour. The solvent was evaporated and the crude material was purified by preparative TLC (eluting system: 70% EtOAc in hexanes) to give 6.7 mg (71%) of the desired product compound 133. MS: [M + 1] = 348.
H ¹ NMR (CDCl ₃ ) δ8.16 (1H, m), 7.92 (1H, s), 7.65 (3H, m), 3.32 (1H, m), 2.46 (3H, s), 1.5 (6H, d, J = 7Hz).
Example 62: Synthesis of compound 126:

The acetamide oxime was azeotroped with toluene three times before use. A 60% NaH dispersion in oil (13 mg, 0.32 mmol) was added to the suspension of acetamide oxime (24 mg, 0.32 mmol) in THF (1 mL). The suspension was stirred at room temperature for 15 minutes. Compound 3 (50 mg, 0.16 mmol) was added. The vial containing the ester was rinsed with DMF (1 mL) and added to the reaction mixture. The resulting brown suspension was stirred at room temperature for 30 minutes and then heated at 70 ° C. for 2 hours. The suspension was quenched with water and the solution was kept in the refrigerator overnight. The solid was recovered by multiple filtrations to give compound 126, the product of 16 mg (31% yield). MS: [M + 1] = 320. H ¹ NMR (CDCl ₃ ) δ8.18 (1H, m), 7.94 (1H, s), 7.67 (3H, m), 2.51 (3H, s), 2.46 (3H, s).
Example 63: Synthesis of compound 125:

Carboxylic acid (30 mg, 0.11 mmol) obtained from compound 3 in THF (0.3 mL) and DCM (0.3 mL), N, O-dimethylhydroxylamine hydrochloride (13 mg, 0.13 mmol), 1 In suspension of -hydroxybenzotriazole hydrate (17 mg, 0.11 mmol) and triethylamine (46 μL, 0.33 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (32 mg, 0. 17 mmol) was added. The solution was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over MgSO _4. Filtration and concentration gave 31.2 mg (88% yield) of an orange solid, which was used in the next step without further purification. MS: [M + 1] = 325.

A solution of 3M ethylmagnesium bromide (0.31 mL, 0.93 mmol) was added to the solution of the above Weinreb amide derivative (31.2 mg, 0.093 mmol) in THF (0.5 mL) cooled to −78 ° C. did. The reaction mixture was stirred at less than −10 ° C. for 60 minutes. It was then quenched with saturated ammonium chloride solution and extracted with EtOAc (twice). The combined extracts were washed with brine, dried over MgSO _4. Crude products were obtained by filtration and concentration. Chromatography (RediSep 4 g silica-gel column, eluted with 80% EtOAc in hexanes) gave 11.1 mg (41% yield) of compound 125. MS: [M + 1] = 294. H ¹ NMR (CDCl ₃ ) δ8.15 (1H, m), 7.76 (1H, s), 7.65 (3H, m), 3.08 (2H, q, J = 7Hz), 2.44 (3H, s), 1.22 ( 3H, t, J = 7Hz).
Example 64: Synthesis of compound 132:

Hydroxylamine hydrochloride (2.01 g, 29 mmol) and potassium carbonate (4 g, 29 mmol) were added to a solution of isobutyronitrile (2.6 mL; 29 mmol) in EtOH (30 mL) and water (10 mL). The resulting suspension was heated at 80 ° C. for 16 hours. The solvent was removed under reduced pressure. The residue was co-evaporated with toluene. Sodium chloride was removed by washing the crude material with EtOH and filtering. The filtrate was evaporated, co-evaporated with toluene several times and dried under reduced pressure to give 2 g (69%) of N-hydroxybutylamidine.

A 60% NaH dispersion in oil (18 mg, 0.46 mmol) was added to a suspension of N-hydroxybutyl amidine (47 mg, 0.46 mmol) in THF (1 mL). The suspension was stirred at room temperature for 30 minutes. Compound 3 (47 mg, 0.15 mmol) in THF (1 mL) was added. The resulting suspension was stirred at room temperature for 30 minutes and then heated at 70 ° C. for 2 hours. After 1 hour, only 50% conversion was observed. After an additional hour, no changes were observed. Reagents such as those described above (N-hydroxybutylamidine and NaH) were further prepared, added to the reaction mixture and heated for an additional 40 minutes. At this point, LCMS indicated that the reaction was complete. The suspension was quenched with water. Addition of some MeOH helped complete dissolution and the solution was extracted with EtOAc (3 times). The combined extracts were washed with brine (3 times) and dried with _ו4. Crude products were obtained by filtration and concentration. Chromatography (RediSep 4g silica-gel column, eluted with EtOAc) gave compound 132, the product of 20 mg (38% yield). MS: [M + 1] = 348. H ¹ NMR (CDCl ₃ ) δ8.18 (1H, d, J = 8Hz), 7.93 (1H, s), 7.69 (3H, m), 3.22 (1H, m), 2.46 (3H, s), 1.43 ( 6H, d, J = 9.5Hz).
Example 65: Synthesis of compound 161:

_{NaHCO 3} (108 mg, 1.28 mmol) was added to a solution of acid (90 mg, 0.32 mmol) obtained from compound 3 in DMF (2 mL) cooled using an ice bath, followed by NBS (114 mg, 1.28 mmol). 0.64 mmol) was added. The solution was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc (3 times). The combined extracts were washed with brine (twice) and dried with _ו4. Crude products were obtained by filtration and concentration. Chromatography (RediSep 4g silica-gel column, eluted with EtOAc) gave 54 mg (53% yield) of product. MS: [M + 1] = 316.

_{TMS-acetylene (71 μL, 0.5 mmol), CuI (2 mg, 0.01 mmol) and PdCl 2} (PPh ₃ ) in a solution of the bromide derivative (30 mg, 0.1 mmol) in dioxane (1 mL) and triethylamine (1 mL). ₂ (7 mg, 0.01 mmol) was added. The solution was heated at 110 ° C. for 6 hours. Additional Pd catalyst (7 mg) and TMS-acetylene (0.2 mL) were added and the reaction mixture was heated for an additional 12 hours. At this point, LCMS showed about 80% conversion. Additional Pd catalyst (7 mg) and TMS-acetylene (0.2 mL) were added and the reaction mixture was heated for an additional 12 hours. LCMS showed a complete conversion. The reaction mixture was then diluted with water and extracted with EtOAc (3 times). The combined extracts were washed with brine (twice) and dried with _ו4. Crude products were obtained by filtration and concentration. Chromatography (RediSep 4 g silica-gel column, eluted with 70% EtOAc in hexanes) gave 23 mg (69% yield) of product. MS: [M + 1] = 334.

MeOH (0.6 mL) and _H 2 O (0.2mL) alkyne derivative in (23 mg, 0.069 mmol) to a solution of was added 0C of KOH (4mg, 0.076mmol). The solution was warmed to room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride solution and extracted with EtOAc (twice). The combined extracts were washed with brine (twice) and dried in י ₄ . Crude product is obtained by filtration and concentration and purified by preparative TLC (eluting system: 80% EtOAc in hexanes) to give compound 161 which is 8.1 mg (45% yield) of product. Obtained. MS: [M + 1] = 262. H ¹ NMR (CDCl ₃ ) δ8.13 (1H, m), 7.76 (1H, s), 7.62 (3H, m), 4.09 (2H, bs), 3.28 (1H, s), 2.44 (3H, s) ..
Example 66: Synthesis of Compound 146:

To a solution of 3-amino-2-methylacrolein (65 mg, 0.76 mmol) in anhydrous THF (2 mL) was added 60% NaH dispersion in oil (30 mg, 0.76 mmol). The suspension was stirred at room temperature for 15 minutes. Compound 115 (50 mg, 0.19 mmol) was added and the reaction mixture was heated at 65 ° C. for 3 hours. The reaction mixture was cooled using an ice bath and water was added. The reaction mixture was stored overnight in the refrigerator. The solid was recovered by filtration to give 27.5 mg (44% yield) of white solid compound 146. MS: [M + 1] = 330. H ¹ NMR (CDCl ₃ ) δ8.66 (2H, s), 8.15 (1H, m), 7.89 (1H, s), 7.65 (3H, m), 2.44 (3H, s), 2.36 (3H, s) ..
Example 67: Synthesis of compound 153:

実施例６８：化合物１１６の合成：

Thionyl chloride (1 mL; 13.8 mmol) and DMF (20 μL) were added to a suspension of acid (30 mg, 0.11 mmol) obtained from compound 3 in dichloroethane (0.2 mL). The resulting solution was heated at 70 ° C. for 1 hour. The solvent was removed. The crude material was dried under reduced pressure. The crude material was suspended in isopropanol (2 mL) and stirred at room temperature for 16 hours. The solvent was evaporated, co-evaporated with methanol and the crude material was purified by preparative TLC (elution system: EtOAc) to give 7.2 mg (21% yield) of compound 153. MS: [M + 1] = 324. H ¹ NMR (CDCl ₃ ) δ8.15 (1H, d, J = 8Hz), 7.81 (1H, s), 7.64 (3H, m), 5.32 (1H, q, J = 7Hz), 2.45 (3H, s) ), 1.43 (6H, d, J = 7Hz).
Scheme 22

Example 68: Synthesis of Compound 116:

An alternative route to the nitrile-substituted imidazole derivative was also performed. As an example, compound 116 was prepared from an imino derivative as shown in Scheme 22. A solution of isocyanate acetonitrile (206 mg, 3.12 mmol) in DMF (7 mL) was cooled to −50 ° C. under a nitrogen atmosphere. KOtBu (320 mg, 2.85 mmol) was added. The mixture was stirred at −50 ° C. for 1 hour. Imine derivatives (prepared in the same format as the imino derivatives shown in Scheme 21 above) (350 mg, 1.24 mmol) were added slowly at −50 ° C. The mixture was warmed to room temperature for 16 hours. The addition of saturated aqueous _NH 4 Cl and it was extracted 3 times with EtOAc. The combined extracts were washed with brine (3 times) and dried with _ו4. Crude products were obtained by filtration and concentration. Chromatography (RediSep 12 g silica-gel column, eluted with 70% EtOAc in hexanes) gave 230 mg (70% yield) of compound 116. MS: [M + 1] = 281. H ¹ NMR (CDCl ₃ ) δ7.92 (1H, dd, J = 3, 8.5Hz), 7.81 (1H, s), 7.61 (1H, dd, J = 4.5, 9Hz), 7.38 (1H, m), 2.47 (3H, s).
Example 69: Synthesis of compound 145:

Hydroxylammonium hydrochloride (17 mg, 0.24 mmol) and potassium carbonate (28 mg, 0) in a suspension of cyanide derivative compound 116 (50 mg, 0.18 mmol) in EtOH (1.6 mL) and water (0.4 mL). .2 mmol) was added. The suspension was heated at 80 ° C. for 30 minutes and then cooled to room temperature. The solid precipitate was collected by filtration to give 37.8 mg (68% yield) of the desired aminooxime product. [M + 1] = 314.

A suspension of amide oxime (10 mg, 0.032 mmol) in acetic anhydride (0.5 mL) was heated at 140 C for 4 hours. The reaction mixture was cooled, EtOH (1 mL) was added to the reaction mixture and it was heated at 80 ° C. for 16 hours. The solvent was evaporated and the crude material was purified by preparative TLC (eluting system: EtOAc) to give 6.6 mg (61% yield) of the desired product compound 145. MS: [M + 1] = 338. H ¹ NMR (CDCl ₃ ) δ7.91 (1H, dd, J = 3.5, 8.5Hz), 7.89 (1H, s), 7.65 (1H, dd, J = 5.5, 10Hz), 7.35 (1H, m), 2.69 (3H, s), 2.45 (3H, s).
Example 70: Synthesis of Compound 149:

CDI (16 mg, 0.096 mmol) was added to a solution of isobutyric acid (30 μL, 0.32 mmol) in THF (0.5 mL). The solution was stirred at room temperature for 2 hours. The above amide oxime derivative (10 mg, 0.032 mmol) was added, and the reaction mixture was heated at 70 C for 45 minutes. The solvent was evaporated, the crude material was suspended in isobutyric acid (1 mL) and heated at 130 ° C. for 3 hours. The solvent was evaporated and the crude material was purified by preparative TLC (eluting system: 80% EtOAc in hexanes) to give 10.6 mg (91%) of the desired product compound 149. MS: [M + 1] = 366. H ¹ NMR (CDCl ₃ ) δ7.90 (1H, dd, J = 3.5, 9Hz), 7.89 (1H, s), 7.66 (1H, dd, J = 4.5, 8.5Hz), 7.36 (1H, m), 3.32 (1H, q, J = 6.5Hz), 2.46 (3H, s), 1.49 (6H, d, J = 8Hz).
Example 71: Synthesis of compound 150:

The suspension of the above amide oxime (10 mg, 0.032 mmol) in trifluoroacetic anhydride (0.5 mL) was heated to reflux for 10 minutes. The solvent was evaporated and the crude material was purified by preparative TLC (eluting system: 80% EtOAc in hexanes) to give 11.8 mg (94%) of the desired product, compound 150. MS: [M + 1] = 392. H ¹ NMR (CDCl ₃ ) δ7.92 (2H, m), 7.69 (1H, dd, J = 5.5, 9.5Hz), 7.39 (1H, m), 2.45 (3H, s).
Example 72: Synthesis of compound 151:

CDI (16 mg, 0.096 mmol) was added to a solution of formic acid (12 μL, 0.32 mmol) in THF (0.5 mL). The solution was stirred at room temperature for 2 hours. The above amide oxime derivative (10 mg, 0.032 mmol) was added, and the reaction mixture was heated at 70 ° C. for 45 minutes. The solvent was evaporated, the crude material was suspended in formic acid (1 mL) and heated at 60 ° C. for 3 hours. The solvent was evaporated and the crude material was purified by preparative TLC (eluting system: 80% EtOAc in hexanes) to give 2.1 mg (20%) of the desired product compound 151. MS: [M + 1] = 324. H ¹ NMR (CDCl ₃ ) δ8.83 (1H, s), 7.92 (1H, dd, J = 3.5, 8Hz), 7.91 (1H, s), 7.65 (1H, dd, J = 4.5, 9Hz), 7.37 (1H, m), 2.45 (3H, s).
Example 73: Synthesis of compound 155:

CDI (14 mg, 0.087 mmol) was added to a solution of propionic acid (22 μL, 0.29 mmol) in THF (0.5 mL). The solution was stirred at room temperature for 1 hour. The above amide oxime derivative (10 mg, 0.032 mmol) in THF (0.5 mL) was added and the reaction mixture was heated at 70 ° C. for 90 minutes. The solvent was evaporated, the crude material was suspended in propionic acid (1 mL) and heated at 130 ° C. for 1 hour. The solvent was evaporated and the crude material was purified by preparative TLC (eluting system: 80% EtOAc in hexanes) to give 9.4 mg (94%) of the desired product compound 155. MS: [M + 1] = 352. H ¹ NMR (CDCl ₃ ) δ7.91 (1H, dd, J = 2, 8.5Hz), 7.88 (1H, s), 7.65 (1H, dd, J = 6, 9.5Hz), 7.36 (1H, m) , 3.01 (2H, q, J = 8.5Hz), 2.46 (3H, s), 1.48 (3H, t, J = 8.5Hz).
Example 74: Synthesis of compound 160:

CDI (14 mg, 0.087 mmol) was added to a solution of pivalic acid (30 mg, 0.29 mmol) in THF (0.5 mL). The solution was stirred at room temperature for 1 hour. The above amide oxime derivative (10 mg, 0.032 mmol) in THF (0.5 mL) was added and the reaction mixture was heated at 70 ° C. for 90 minutes. The solvent was evaporated, the crude material was suspended in acetic acid (1 mL) and heated to reflux for 3 hours. The solvent was evaporated and the crude material was purified by preparative TLC (eluting system: 80% EtOAc in hexanes) to give 7.4 mg (67%) of the desired product, compound 160. MS: [M + 1] = 380. H ¹ NMR (CDCl ₃ ) δ7.90 (1H, dd, J = 2.7, 9Hz), 7.88 (1H, s), 7.65 (1H, dd, J = 4.5, 9Hz), 7.35 (1H, m), 2.47 (3H, s), 1.53 (9H, s).
Example 75: Synthesis of Compound 143:

A solution of KOtBu (40 mg, 0.36 mmol) in DMF (3 mL) was cooled to −50 ° C. under a nitrogen atmosphere. p-Tolueneslfoneylmethyl isocyanide (76 mg, 0.39 mmol) was added. The mixture was stirred at −50 ° C. for 1 hour. The imino derivative from Scheme 22 (50 mg, 0.18 mmol) was added and the mixture was warmed to room temperature for 16 hours. A saturated _{aqueous solution of NH 4} Cl was added and it was extracted 5 times with EtOAc. The combined extracts were washed with brine (3 times) and dried with _ו4. Crude products were obtained by filtration and concentration. Chromatography (RediSep 4g silica-gel column, eluted with 70% EtOAc in hexanes) followed by preparative TLC (elution system: 30% EtOAc in DCM) in a 22.2 mg (30% yield) white solid. A compound 143 was obtained. MS: [M + 1] = 410.
H ¹ NMR (CDCl ₃ ) δ7.91 (2H, d, J = 8Hz), 7.87 (1H, dd, J = 2.5, 8.5Hz), 7.74 (1H, s), 7.65 (1H, dd, J = 5.5) , 9Hz), 7.34 (3H, m), 2.50 (3H, s), 2.42 (3H, s).
Example 76: Synthesis of Compound 144:

To 3-ethoxymethacrolein (100 mg, 0.88 mmol) was added 7N ammonia in methanol (1.3 mL, 8.8 mmol). The solution was stirred at room temperature for 16 hours. The solvent was evaporated and the crude yellow solid corresponding to 3-amino-2-methylacrolein was used in the next step without further purification.

実施例７７：化合物１２１の合成：

60% NaH dispersion in oil (6 mg, 0.16 mmol) was added to a solution of 3-amino-2-methylacrolein (7 mg, 0.087 mmol) in anhydrous THF (1 mL). The suspension was stirred at room temperature for 15 minutes. A cyanide derivative (22 mg, 0.079 mmol) in THF (1 mL) was added and the reaction mixture was heated at 65 ° C. for 1 hour. As described above, a new batch of reagents was prepared with 3-amino-2-methylacrolein (20 mg) and NaH (20 mg) in THF (1 mL) and added to the reaction mixture above. , It was heated at 65 ° C. for an additional hour. LCMS showed the reaction was complete. The reaction mixture was quenched with methanol. The solvent was evaporated. The crude material was suspended in water and the solid was recovered by filtration to give 5.2 mg (19% yield) of the light red solid compound 144. MS: [M + 1] = 348. H ¹ NMR (CDCl ₃ ) δ8.67 (2H, s), 7.90 (1H, d, J = 9.5Hz), 7.85 (1H, s), 7.65 (1H, dd, J = 4.5, 9Hz), 7.34 ( 1H, m), 2.44 (3H, s), 2.36 (3H, s).
Scheme 23

Example 77: Synthesis of Compound 121:

_{I-Pr 2} NEt (5.6 mL, 32.4 mmol) was added to a solution of 1,2,4-triazole, (2.03 g, 29.4 mmol) in _{anhydrous CH 3} CN (20 mL) at 0 ° C. .. Once all triazoles were dissolved, POCl ₃ (0.82 mL, 8.8 mmol) and compound 16'(1 g, 3.68 mmol) were added. The mixture was stirred at 0 ° C. for 2 hours. The resulting solution was heated in an oil bath at 80 ° C. for 16 hours. The mixture was cooled using an ice bath, diluted with EtOAc and water was added. It was extracted 3 times with EtOAc. The combined extracts were washed with brine, dried over MgSO _4. Filtration and concentration gave 1.05 g (88% yield) of an orange solid, which was used as is in the next step. MS: [M + 1] = 324.

A solution of KOtBu (696 mg, 6.2 mmol) in DMF (15 mL) was cooled to −50 ° C. under a nitrogen atmosphere. Ethyl acetate (0.75 mL, 6.8 mmol) was added slowly. The mixture was stirred at −50 ° C. for 1 hour. The crude product from step 1 (1 g, 3.1 mmol) was added and the mixture was heated to room temperature for 18 hours. The addition of saturated aqueous _NH 4 Cl, which was extracted 8 times with EtOAc. The combined extracts were washed with brine (3 times) and dried with _ו4. Crude products were obtained by filtration and concentration. Chromatography (RediSep 24 g silica-gel column, eluted with 70% EtOAc in hexanes) gave 950 mg (83% yield) of product. MS: [M + 1] = 368.

LiBH4 (2M in THF, 0.66 mL, 1.3 mmol) was added to a solution of diester (200 mg, 0.54 mmol) in anhydrous THF (4 mL) stirred at room temperature under a nitrogen atmosphere. The reaction mixture was stirred under a nitrogen atmosphere for 24 hours. A mixture of EtOAc / EtOH (3 mL / 3 mL) was added to the reaction mixture and it was concentrated. The residue was dissolved in MeOH and silica gel was added. After evaporating the volatile solvent, the solid was loaded into a RediSep 4g silica-gel column. The desired product was eluted with CH2Cl2 / MeOH at 10: 1 v / v. The diol was obtained as a solid (60 mg, 39% yield). MS: [M + 1] = 284.

The diol (60 mg, 0.21 mmol) was suspended in 5 mL of AcOH at 33% HBr and heated at 80 ° C. for 18 hours. The solution was cooled using an ice bath and diluted with EtOAc. Saturated aqueous NaHCO3 solution was added slowly. The solution was extracted with EtOAc (3 times), the combined organic phases were washed with brine and dried over 00544. The crude product was obtained by filtration and concentration and used in the next step without further purification. MS: [M + 1] = 408.

To a solution of the dialkylbromid derivative (0.21 mmol) in EtOAc (10 mL) and MeOH (10 mL) was added wet 10% Pd / C (catalytic amount) and the resulting suspension was placed in a hydrogen atmosphere for 60 hours. Stirred. The suspension was filtered through Celite and the resulting solution was concentrated. The crude product is purified by multiple preparative TLCs (eluting system: 3% MeOH in EtOAc) to give 6.2 mg (12% yield for 2 steps) of compound 121, which is the desired product. Got MS: [M + 1] = 252. H ¹ NMR (CDCl ₃ ) δ8.09 (1H, m), 7.74 (1H, s), 7.56 (3H, m), 7.90 (2H, m), 2.42 (3H, s), 2.29 (3H, s) ..
Example 78: Synthesis of Compound 135:

Compound 135 was synthesized in a manner similar to compound 121 as follows: _{i-Pr 2 in} a solution of 1,2,4-triazole (952 mg, 13.8 mmol) in _{anhydrous CH 3 CN (20 mL) at 0 ° C.} NEt (2.6 mL, 15.2 mmol) was added. Once all triazoles were dissolved, POCl ₃ (0.45 mL, 4.8 mmol) and lactam ester (1 g, 3.45 mmol) were added. The mixture was stirred at 0 ° C. for 2 hours. The resulting solution was heated in an oil bath at 80 ° C. for 16 hours. The mixture was cooled using an ice bath, diluted with EtOAc and water was added. It was extracted 3 times with EtOAc. The combined extracts were washed with brine, dried over MgSO _4. Filtration and concentration gave 1.03 g (87% yield) of an orange solid, which was used as is in the next step. MS: [M + 1] = 342.
A solution of KOtBu (658 mg, 5.9 mmol) in DMF (15 mL) was cooled to −50 ° C. under a nitrogen atmosphere. Ethyl acetate (0.71 mL, 6.5 mmol) was added slowly. The mixture was stirred at −50 ° C. for 1 hour. The crude product from step 1 (1 g, 2.9 mmol) was added and the mixture was heated to room temperature for 18 hours. The addition of saturated aqueous _NH 4 Cl, which was extracted 8 times with EtOAc. The combined extracts were washed with brine (3 times) and dried with _ו4. Crude products were obtained by filtration and concentration. Chromatography (RediSep 24 g silica-gel column, eluted with 70% EtOAc in hexanes) gave 1.02 g (90% yield) of product. MS: [M + 1] = 386.

_{LiBH 4} (2M in THF, 3.1 mL, 6.24 mmol) was added to a solution of the diester (600 mg, 1.56 mmol) in anhydrous THF (8 mL) stirred at room temperature under a nitrogen atmosphere. The reaction mixture was stirred under a nitrogen atmosphere for 24 hours. A mixture of EtOAc / EtOH (10 mL / 10 mL) was added to the reaction mixture and it was concentrated. The residue was dissolved in MeOH and silica gel was added. After evaporating the volatile solvent, the solid was loaded into a RediSep 12g silica-gel column. The desired product was eluted with _{CH 2} Cl ₂ / MeOH at 10: 1 v / v. The diol was obtained as a solid (187 mg, 40% yield). MS: [M + 1] = 302.

The diol (80 mg, 0.27 mmol) was suspended in 7 mL of AcOH at 33% HBr and heated at 80 ° C. for 48 hours. The solution was cooled using an ice bath and diluted with EtOAc. Saturated NaHCO ₃ aqueous solution was added slowly. The solution was extracted (3 times), the combined organic phases were washed with brine, dried over MgSO _4. Filtration, concentration and co-evaporation with toluene gave 100 mg (88% yield) of a beige solid, which was used in the next step without further purification. MS: [M + 1] = 426.

To a solution of the dialkylbromid derivative (70 mg, 0.16 mmol) in EtOAc (10 mL) and MeOH (10 mL) was added 10% Pd / C (catalytic amount) and the suspension obtained was 48 in a hydrogen atmosphere. Stir for hours. The suspension was filtered through Celite and the resulting solution was concentrated. The crude product was purified by multiple preparative TLCs (elution system 1: 75% EtOAc in hexanes; elution system 2: 5% MeOH in EtOAc; elution system 3: EtOAc) at 4.1 mg (10). % Yield) of the desired product, compound 135. MS: [M + 1] = 270. H ¹ NMR (CDCl ₃ ) δ7.84 (1H, dd, J = 2.5, 9Hz), 7.70 (1H, s), 7.54 (1H, dd, J = 5, 8Hz), 7.30 (1H, m), 2.42 (3H, s), 2.28 (3H, s).
Example 79: Synthesis of compound 134:

実施例８０：化合物１３７の合成：

Freshly prepared NaOEt 2M solution (75 μL) in a suspension of the R = H dialkylbromid derivative (30 mg, 0.074 mmol) described in Scheme 23, heated at 80 ° C. in EtOH (1 mL). , 0.15 mmol) was added. The solution was heated for 10 minutes. The solvent was evaporated. The crude material was suspended in EtOAc and filtered. The filtrate was concentrated and purified by preparative TLC (eluting system: EtOAc) to give 3.1 mg (12% yield) of the desired product, compound 134. MS: [M + 1] = 340.
Scheme 24

Example 80: Synthesis of Compound 137:

In a solution of 5-fluoro-2-nitrobenzoic acid (6.6 g, 35.66 mmol) in dichloromethane (100 mL), DIPEA (9.22 g, 71.3 mmol), HOBt (6.0 g, 39.2 mmol) and. EDCI (10.2 g, 53.5 mmol) was added. After stirring for about 15 minutes, a solution of 2,4-dimethoxybenzylamine (5.96 g, 35.66 mmol) in dichloromethane (50 mL) was added dropwise to the reaction mixture under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction mixture was washed successively with 1N HCl (100 mL), saturated NaHCO ₃ (100 mL) and brine (100 mL). The organic phase was then dried with י ₄ . Filtration and removal of the solvent under reduced pressure gave a yellowish solid. wt: 9.3 g (78%). MS: [M + 1] = 335.

Zn powder was added to the nitrobenzene analog (9.3 g, 27.8 mmol) suspended in a solvent mixture of HOAc / THF / MeOH / H _{2 O (25/100/50/25 mL) at room temperature and stirred.} The mixture was heated to 70 ° C. for 20 hours, cooled and filtered. The solid was rinsed with THF and the combined filtrate was concentrated under reduced pressure. _{Saturated NaHCO 3} was added slowly and carefully to the resulting slurry until the pH reached 7-8 to prevent the formation of excess foam. The mixture was extracted with EtOAc (3 times); the combined organic layers were washed with brine and dried over 00544. Filtration was performed to remove the solvent to give the crude amine product as a dark brown sticky paste. wt: 8.7 g.

Triethylamine (3.37 g, 33.4 mmol) was added to a solution of aniline (8.7 g) from the above in dichloromethane (150 mL). The mixture was cooled using an ice bath and treated with bromoacetyl chloride (4.81 g, 30.6 mmol) under a nitrogen atmosphere. The ice bath was removed and the mixture was left agitated for 72 hours. The reaction mixture was concentrated under reduced pressure and the resulting slurry was _{treated with Et 2} O (100 mL) and water (100 mL). The product precipitate was collected by filtration and dried to give 5.6 g of product as a brown solid. The Et ₂ O layer was separated from the aqueous layer, diluted with DCM (50 mL), washed with brine and dried with י ₄ . Filtration to remove the solvent gave 5.3 g of additional product as a foamy brown solid. Total wt: 11 g (100%).

To a solution of the bromide in DMF (550mL) _(11g), was added _{K 2 CO 3 (7.1g, 51.7mmol} ). The mixture was heated at 50 ° C. for 48 hours. The mixture was cooled to room temperature and the inorganic solid was filtered off. The filtrate was concentrated under reduced pressure, treated with water / MeOH (60/10 mL) and extracted with DCM (3 times); the combined organic layers were washed with brine and dried with י ₄ . After filtration to remove the solvent, silica gel column chromatography with 5-50% EtOAc in DCM gave 3.2 g (36%) 7-membered lactam as a brownish solid. MS: [M + 1] = 345.

T-BuOK (0.645 g, 5.75 mmol) was added to lactam (1.32 g, 3.83 mmol) dissolved in THF (20 mL) and DMF (3 mL) at −20 ° C. and stirred. After stirring at −20 ° C. for 30 minutes, diethyl chlorophosphate (1.19 mL, 6.89 mmol) was added dropwise and the mixture was stirred for 3 hours while heating from −20 ° C. to 20 ° C. The reaction mixture was cooled to −78 ° C., ethyl isocyanoacetate (0.791 mL, 6.89 mmol) was added thereto, then t-BuOK (0.645 g, 5.75 mmol) was added, and stirring was continued overnight. During this time, the temperature reached room temperature. The reaction _{was quenched with saturated NH 4} Cl and extracted with EtOAc (twice); the combined organic solutions were washed with brine and dried with regsvr ₄ . Filtration to remove the solvent gives the crude product, which is purified by silica gel column chromatography with 15-100% EtOAc in DCM in wt: 0.861 g (47%). Obtained as a brown solid. MS: [M + 1] = 440.

Trifluoroacetic acid (5 mL) was added to the imidazole ester (861 mg) from the above in dichloromethane (5 mL) at 0 ° C., and then trifluoromethanesulfonic acid (0.345 mL) was added. The mixture was warmed to room temperature, stirred for 3 hours and then concentrated to give a residue, which was dissolved in dichloromethane (50 mL). _{Saturated NaHCO 3} (50 mL) was added thereto, and the mixture was stirred for 20 minutes. The pH of the upper aqueous layer was determined to be basic, it was separated and extracted with DCM (3 times); the combined DCM solutions were washed with brine and dried with י ₄ . Filtration to remove the solvent gave 0.58 g (100%) of lactam as a yellowish solid. MS: [M + 1] = 290.

_{POCl 3} (209.1 mg, 0.723 mmol) to lactam (209.1 mg, 0.723 mmol) and N, N-dimethyl-p-toluidine (234.7 mg, 1.74 mmol) agitated in chlorobenzene (2.5 mL) under nitrogen. 133.0 mg, 0.867 mmol) was added. The reaction was then heated at 135 ° C. for 2 hours. After cooling to room temperature, phenoxyacetic acid hydrazide (189.0 mg, 1.08 mmol) was added, followed by DIPEA (0.455 mL). The reaction was stirred at room temperature for 30 minutes and then heated at 100 ° C. for 60 minutes. The reaction mixture was cooled, saturated NH ₄ Cl (aqueous solution) was added, and the mixture was extracted 3 times with ethyl acetate; the combined organic layers were washed with brine and dried with chloroform ₄ . After filtration and concentration, the product was isolated by ISCO flash column chromatography with 0-10% MeOH in EtOAc. Compound 137 at wt: 116.7 mg (36%) as a yellowish film-like solid. MS: [M + 1] = 420.
Example 81: Synthesis of compound 156:

LiOH (69.7 mg, 2) of ethyl ester compound 137 (244.2 mg, 0.582 mmol) in a solvent system of THF / water / MeOH (total 6.0 mL, 6/5/1 ratio) for 4 hours at room temperature. .91 mmol), concentrated under reduced pressure, acidified to pH about 3, and the precipitate was recovered by filtration. After washing with water and drying, 179.3 mg (79%) of acid was obtained as a yellowish solid. MS: [M + 1] = 392.

EdCI (21.3 mg, 0.11 mmol), DMAP (6.7 mg, 0.0552 mmol) and isopropyl were added to the acid (10.8 mg, 0.0276 mmol) stirred in DCM (0.1 ml) at room temperature. Alcohol (13.2 mg, 0.221 mmol) was added. After 12 hours, the reaction was diluted with EtOAc, washed with saturated NaHCO _3; the aqueous layer was separated, extracted with EtOAc, the combined organic layers were washed with brine, dried over MgSO _4. The concentrate was filtered and purified by preparative TLC with 10% MeOH in EtOAc to give 8.7 mg (73%) of isopropyl ester compound 156 as a yellowish foam solid. MS: [M + 1] = 434.
Example 82: Synthesis of compound 138:

Acetamide oxime (10.7 mg, 0.144 mmol) was azeotroped with toluene four times and added to ethyl ester compound 137 (9.5 mg, 0.0226 mmol). After adding THF (0.3 mL), NaH 60% oil suspension (4.5 mg, 0.112 mmol) was added. The reaction mixture is stirred at room temperature for 30 minutes, then heated at 70 ° C. for 2 hours, cooled to room temperature, the solvent is removed under reduced pressure and water (1.5 mL) is added to give the reaction product. It was quenched, stirred for 20 minutes and cooled to 4 ° C. The precipitate was collected by filtration, washed with water and dried to give 5.2 mg (59%) of compound 138, an oxadiazole product, as a pale yellow solid. MS: [M + 1] = 430.
Example 83: Synthesis of Compound 141:

By synthesizing the compound of Example 83 using isobutyramide oxime instead of acetamide oxime in a synthetic route similar to that described in Example 82, the compound of Example 83 is made into a yellowish solid. Obtained: MS: [M + 1] = 458.
Example 84: Synthesis of compound 157:

Carbonyldiimidazole (49.9 mg, 0.308 mmol) was added to the acid (60.2 mg, 0.154 mmol) prepared in Example 81 above, which was stirred in DCM (0.7 mL) at room temperature. did. The mixture was stirred for 40 minutes, then cooled to 0 ° C., ammonia (0.112 ml) was added and the mixture was warmed to room temperature with continued stirring overnight. The reaction was concentrated, water (8 mL) was added and stirred well for 30 minutes. The resulting precipitate was collected by filtration, washed with water and dried to give 51.1 mg (85%) of the primary amide as a brownish solid. MS: [M + 1] = 391.

_{The amide from the above (51.1 mg) was treated with POCl 3} (200.8 mg, 1.31 mmol) in 1,4-dioxane (0.9 mL) at 90 ° C. for 14 hours. After cooling to room temperature, the reaction _{was carefully quenched with saturated NaHCO 3} (5 mL) and stirred for 20 minutes. The precipitate was collected by filtration, washed with water and dried to give 40.9 mg (85%) of compound 157, the nitrile product, as a brownish solid. MS: [M + 1] = 373.
Example 85: Synthesis of Compound 147:

The above nitrile round bottom flask (45.8mg, 0.123mmol), hydroxylamine hydrochloride _{(14.5mg, 0.209mmol), K 2} CO 3 (22.3mg, 0.161mmol), ethanol (0.6 mL ) And water (0.15 mL) were added. The reaction mixture was heated at 80 ° C. for 30 minutes, cooled and concentrated under reduced pressure. The resulting slurry was treated with water (1.5 mL) and sonicated to aid mixing, stirring at room temperature for 1 hour and then cooling to 4 ° C. The resulting precipitate was collected by filtration, washed with cold water (1 mL) and dried to give 40.8 mg (82%) of the adduct as an off-white solid. MS: [M + 1] = 406.

Isobutyric acid (31.4 mg, 0.582 mmol) was treated with carbonyldiimidazole (28.4 mg, 0.175 mmol) in THF (0.5 mL) for 2 hours. The above N-hydroxycarboxamide adduct (11.8 mg, 0.0291 mmol) was added, and the reaction product was stirred at room temperature for 30 minutes. Additional isobutyric acid (0.5 mL) was added and the reaction mixture was heated at 110 ° C. for 16 hours, cooled, saturated NaHCO ₃ (8 mL) was added and extracted with EtOAc (3 times); combined organic layers. It was washed with brine, dried over MgSO _4. Preparative TLC (5% MeOH in EtOAc) of the concentrated filtrate gave 11.2 mg (84%) of oxadiazole compound 147 as a white solid. MS: [M + 1] = 458.
Example 86: Synthesis of Compound 148:

The compound of Example 86 was obtained as a white solid by synthesizing the compound of Example 86 using acetic acid instead of isobutyric acid in a synthetic route similar to that described in Example 85: MS. : [M + 1] = 430.
Example 87: Synthesis of compound 158:

The compound of Example 87 was obtained as a white solid by synthesizing the compound of Example 87 using propionic acid instead of isobutyric acid in a synthetic route similar to that described in Example 85: MS: [M + 1] = 444.
Example 88: Synthesis of Compound 159:

実施例８９：化合物１６２の合成：

Trifluoroacetic anhydride (196.9 mg, 0.938 mmol) was suspended in THF (0.2 mL) at room temperature and added to the stirred N-hydroxycarboxamide adduct (19.0 mg, 0.0469 mmol). .. After stirring for 30 minutes, the reaction was heated to 70 ° C. for 1 hour, cooled to room temperature, diluted with EtOAc (10 mL), saturated NaHCO ₃ was added and stirred for 30 minutes. The aqueous layer was separated and extracted with EtOAc (once); the combined organic layers were washed with brine and dried with ethyl ₄ . The paste was obtained by filtration to remove the solvent, to which nBuOH (5 ml) and HOAc (0.5 mL) were added. It was heated at 115 ° C. for 16 hours, cooled, concentrated under reduced pressure, diluted with EtOAc _{, washed with saturated NaHCO 3} and brine, and dried with regsvr ₄ . Preparative TLC (5% MeOH in EtOAc) of the concentrated filtrate gave 11.5 mg (51%) of the desired trifluoromethyloxadiazole analog compound 159 as a yellowish solid. MS: [M + 1] = 484.
Scheme 25

Example 89: Synthesis of Compound 162:

To BuOK (240.2 mg) was added to lactam 62 (503.4 mg, 1.42 mmol) agitated in THF (2.9 ml) and DMF (0.8 mL) at −20 ° C. After stirring for 30 minutes, diethyl chlorophosphate (377.7 mg, 2.12 mmol) was added dropwise, and the reaction mixture was slowly warmed to 8 ° C. over 3 hours and then cooled to −20 ° C. 2.26 mL (2.26 mmol) of oxadiazole isocyanate (see JMC, 1996, 39, 170; prepared as a 1 M THF solution) was added. The reaction mixture was further cooled to −78 ° C., tBuOK (238.4 mg) was added and the reaction was slowly warmed to room temperature overnight. The addition of saturated _NH 4 Cl (5 mL), the mixture was extracted with EtOAc (2 times), washed with brine, dried over MgSO _4. After filtration and concentration, the product was isolated by silica gel column chromatography using gradient elution of 0-10% MeOH in EtOAc to give 246.0 mg of the imidazole product as a yellowish solid. MS: [M + 1] = 462.

The imidazole (246.0 mg, 0.533 mmol) obtained above was stirred in DCM (3 ml). After adding trifluoroacetic acid (3 mL), trifluoromethylsulfonic acid (160.0 mg, 1.07 mmol) was added. After stirring for 3 hours, the reaction is diluted with DCM (20 mL) and _{washed with saturated NaHCO 3} ; the aqueous layer is separated and extracted with DCM (twice); the combined DCM solutions are washed with brine. dried over MgSO _4. Filtration and removal of the solvent under reduced pressure gave 208.7 mg of crude lactam product as a yellowish flaky solid. [M + 1] = 312.

Lactam (22.5 mg, 0.0723 mmol) and N, N-dimethyl-p-toluidine (51.8 mg, 0.383 mmol) obtained above, stirred in chlorobenzene (0.45 mL) under a nitrogen atmosphere. ), Phosphorus oxychloride (29.9 mg, 0.195 mmol) was added. The reaction mixture was heated at 135 ° C. for 3 hours and then cooled to room temperature. Diisopropylethylamine (75.7 mg, 0.586 mmol) and phenoxyacetic acid hydrazide (50.1 mg, 0.302 mmol) were added and the reaction mixture was heated at 100 ° C. for 14 hours, cooled to room temperature and saturated with NH ₄ Cl. Divided into EtOAc. The aqueous layer was separated and extracted with EtOAc; the combined EtOAc solution was washed with brine, dried over MgSO _4. After filtration and concentration, the product compound 162 was isolated as a yellowish solid by silica gel column chromatography using gradient elution of 0-10% MeOH in EtOAc. Wt: 11.8 mg (37%). MS: [M + 1] = 442.
Example 90: Synthesis of Compound 163:

The compound of Example 90 is yellowed by synthesizing the compound of Example 90 using 4-fluorophenoxyacetic acid hydrazide instead of phenoxyacetic acid hydrazide in a synthetic route similar to that described in Example 89. Obtained as a yellowish solid: MS: [M + 1] = 460.
Example 91: Synthesis of Compound 164:

A yellowish solid of the compound of Example 91 by synthesizing the compound of Example 91 using methoxyacetic acid hydrazide instead of phenoxyacetic acid hydrazide in a synthetic route similar to that described in Example 89. Obtained as: MS: [M + 1] = 380.
Example 92: Synthesis of compound 165:

Preparation of benzyloxyacetic acid hydrazide: Carbonyldiimidazole (1.52 g, 9.39 mmol) was added to benzyloxyacetic acid (1.2 g, 7.22 mmol) stirring in THF (60 mL) at 0 ° C. The ice bath was removed and stirring was continued for 1 hour. The resulting turbid solution was added to hydrazine (0.927 g, 28.9 mmol) stirring in THF (40 mL) at room temperature. After 16 hours, the slurry was concentrated and the reaction mixture, it was added water (120 mL), and extracted with DCM (3 times); the combined DCM solution was washed with brine, dried over MgSO _4. Filtration to remove the solvent gave 0.908 g (70%) of hydrazide as a clear viscous oil. This was azeotroped with toluene several times before use.
The compound of Example 92 was yellowish by synthesizing the compound of Example 92 using benzyloxyacetic acid hydrazide instead of phenoxyacetic acid hydrazide in a synthetic route similar to that described in Example 89. Obtained as solid: MS: [M + 1] = 456.
Example 93: Synthesis of Compound 166:

実施例９４：化合物１６９の合成：

Compound 165 (58.5 mg, 0.128 mmol) from the above was treated with 10% Pd-C (catalyst) in EtOAc (4 mL) and MeOH (4 mL) under a hydrogen atmosphere for 2 hours. The catalyst was removed by filtration through Celite. Concentrated HCl (0.89 mL) was added to the filtrate and the mixture was stirred at room temperature for 16 hours. Adding an excess amount of _Na 2 CO ₃ (aq), the solution extracted (2 times) EtOAc; the washed combined organic solutions with brine, dried over MgSO _4. Preparative TLC of the concentrated filtrate with 15% MeOH in EtOAc gave 14.9 mg of the primary amide ([M + 1] = 417) as a yellowish solid. The primary amide was treated with phosphorus oxychloride (54.9 mg, 0.358 mmol) in 1,4-dioxane (1 mL) at 90 ° C. for 14 hours. Upon cooling, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO _3; the aqueous layer was separated, extracted with EtOAc (1 ×), the combined organic solution was washed with brine, dried over MgSO ₄ .. Preparative TLC of the concentrated filtrate with 5% MeOH in EtOAc gave 5.2 mg of compound 166, the desired nitrile product, as a white needle. [M + 1] = 399.
Scheme 26

Example 94: Synthesis of compound 169:

TBuOK (1.05 g, 9.36 mmol) was added to lactam 62 (2.23 g, 6.24 mmol) agitated in THF (10 mL) and DMF (3 mL) at −20 ° C. After stirring for 30 minutes, diethyl chlorophosphate (1.66 g, 9.36 mmol) was added dropwise, and the reaction mixture was slowly warmed to 8-10 ° C over 3 hours and then cooled to −20 ° C. 10.0 ml (10.0 mmol) of oxadiazole isocyanate (see JMC, 1996, 39, 170; prepared as a 1 M THF solution) was added. The reaction mixture was further cooled to −78 ° C., tBuOK (1.05 g, 9.36 mmol) was added and the reaction was slowly warmed to room temperature overnight. The addition of saturated _NH 4 Cl (20 mL), the mixture was extracted with EtOAc (3 times), washed with brine, dried over MgSO _4. Once filtered and concentrated, the product is isolated by silica gel column chromatography using gradient elution of 10-100% EtOAc in DCM to give 1.07 g (35%) of the imidazole product a yellowish foam. Obtained as a solid. MS: [M + 1] = 490.

The imidazole (1.07 g, 2.18 mmol) obtained above was stirred in DCM (11 mL). After adding trifluoroacetic acid (11 mL), trifluoromethylsulfonic acid (0.656 g, 4.37 mmol) was added. After stirring for 4 hours, the reaction is concentrated under reduced pressure, diluted with DCM (50 mL) _{, washed with saturated NaHCO 3} ; the aqueous layer is separated and extracted with DCM (twice); combined DCM solutions. It was washed with brine, dried over MgSO _4. Filtration and removal of the solvent under reduced pressure gave 0.872 g of crude lactam product as a brownish solid. [M + 1] = 340.

Lactam (45.0 mg, 0.133 mmol) and N, N-dimethyl-p-toluidine (89.6 mg, 0.663 mmol) obtained above, stirred in chlorobenzene (0.60 mL) under a nitrogen atmosphere. ), Phosphorus oxychloride (51.0 mg, 0.333 mmol) was added. The reaction mixture was heated at 135 ° C. for 3 hours and then cooled to room temperature. Diisopropylethylamine (137.5 mg, 1.06 mmol) and methoxyacetic acid hydrazide (83.1 mg, 0.798 mmol) were added and the reaction mixture was heated at 100 ° C. for 4 hours, cooled to room temperature and diluted with EtOAc. Saturated NaHCO ₃ , washed with brine and dried with י ₄ . After filtration and concentration, the product compound 169 was isolated as a brownish solid by silica gel column chromatography using gradient elution of 0-13% MeOH in EtOAc. Wt: 14.3 mg (26%). MS: [M + 1] = 408.
Example 95: Synthesis of compound 171:

A yellowish solid of the compound of Example 95 by synthesizing the compound of Example 95 using phenoxyacetic acid hydrazide instead of methoxyacetic acid hydrazide in a synthetic route similar to that described in Example 94. Obtained as: MS: [M + 1] = 470.
Example 96: Synthesis of Compound 172:

A compound of Example 96 was prepared by synthesizing the compound of Example 96 using 4-fluoro-phenoxyacetic acid hydrazide instead of methoxyacetic acid hydrazide in a synthetic route similar to that described in Example 94. Obtained as a yellowish solid: MS: [M + 1] = 488.
Example 97: Synthesis of Compound 173:

A yellowish solid of the compound of Example 97 by synthesizing the compound of Example 97 using ethoxyacetate hydrazide instead of methoxyacetic acid hydrazide in a synthetic route similar to that described in Example 94. Obtained as: MS: [M + 1] = 422.
Example 98: Synthesis of Compound 174:

A compound of Example 98 was prepared by synthesizing the compound of Example 98 using 2-fluoro-phenoxyacetic acid hydrazide instead of methoxyacetic acid hydrazide in a synthetic route similar to that described in Example 94. Obtained as a yellowish solid: MS: [M + 1] = 488.
Example 99: Synthesis of compound 175:

The compound of Example 99 was prepared by synthesizing the compound of Example 99 using 2-chloro-phenoxyacetic acid hydrazide instead of methoxyacetic acid hydrazide in a synthetic route similar to that described in Example 94. Obtained as a yellowish solid: MS: [M + 1] = 504.
Example 100: Synthesis of Compound 176:

Preparation of 3-pyridyloxyacetate hydrazide: A solution of ethyl 3-pyridyloxyacetate (0.50 g, 2.76 mmol) and hydrazine (0.31 g, 9.66 mmol) in isopropyl alcohol (35 mL) at 85 ° C. 30 It was heated for hours, cooled and concentrated under reduced pressure. The resulting white solid was dissolved in a small amount of saturated NaCl solution and repeatedly extracted with EtOAc. The combined organic solution was dried over MgSO _4. Filtration was performed to remove the solvent to give 177 mg of the desired hydrazide acetate as a white solid. Residual water was removed by azeotropic boiling with toluene.
The compound of Example 100 is yellowed by synthesizing the compound of Example 100 using 3-pyridyloxyacetate hydrazide instead of methoxyacetic acid hydrazide in a synthetic route similar to that described in Example 94. Obtained as a yellowish solid: MS: [M + 1] = 471.
Example 101: Synthesis of compound 177:

Off-whitening the compound of Example 101 by synthesizing the compound of Example 101 using 1-naphthoxyacetic acid hydrazide instead of methoxyacetic acid hydrazide in a synthetic route similar to that described in Example 94. Obtained as a solid of: MS: [M + 1] = 520.
Example 102: Synthesis of compound 179:

The compound of Example 102 is yellowed by synthesizing the compound of Example 102 using 3-fluorophenoxyacetic acid hydrazide instead of methoxyacetic acid hydrazide in a synthetic route similar to that described in Example 94. Obtained as a yellowish solid: MS: [M + 1] = 488.
Example 103: Synthesis of Compound 178:

The above oxadiazolylimidazole lactam (57.5 mg, 0.169 mmol) and N, N-dimethyl-p-toluidine (114.6 mg, 0.847 mmol) stirred in chlorobenzene (0.70 ml) under a nitrogen atmosphere. ), Phosphorus oxychloride (64.8 mg, 0.422 mmol) was added. The reaction mixture was heated at 135 ° C. for 3 hours and then cooled to room temperature. Diisopropylethylamine (174.7 mg, 1.35 mmol), t-BuOH (0.3 ml) and 2-hydroxyacetate hydrazide (91.3 mg, 1.01 mmol) were added. The reaction mixture was stirred at room temperature for 20 minutes, then heated at 50 ° C. for 1 hour, then heated at 80 ° C. for 1 hour, and finally heated at 100 ° C. overnight. Upon cooling to room temperature, the reaction was diluted with EtOAc, washed with brine, dried over MgSO _4. Silica gel column chromatography using gradient elution of 0-20% MeOH in EtOAc in the concentrated filtrate gave the desired hydroxymethyltriazole product as a yellowish solid. Wt: 18.1 mg (27%). MS: [M + 1] = 394.

実施例１０４：化合物１６８の合成：

Hydroxymethyltriazole (18.1 mg, 0.046 mmol), cyclopentyl bromide (274.0 mg, 1.84 mmol) and HMPA (16.5 mg, 0.092 mmol) from above, stirred in THF (0.5 ml). ), NaH (60% suspension; 18.4 mg, 0.46 mmol) was added. After 10 minutes, the reaction was heated for 6 hours at 100 ° C., cooled, quenched with saturated NaHCO _3, extracted with EtOAc (2 times), washed with brine, dried over MgSO _4. A preparative TLC of the concentrated filtrate with 8% MeOH in EtOAc gave 5.5 mg (26%) of the desired ether compound 178 as a yellowish solid. [M + 1] = 462.
Scheme 27

Example 104: Synthesis of Compound 168:

In a suspension of benzyl glycinate hydrochloride (5 g, 24.8 mmol) in DCM (100 mL), EDC. HCl (6.2 g, 33.2 mmol) and triethylamine (5.2 mL, 37.2 mmol) were added. The suspension was cooled to −50 ° C. and then formic acid (1.4 mL, 37.2 mmol) in DCM (5 mL) was added. The reaction mixture was stirred at −50 C for 1 hour and then at 4 ° C. for 3 hours. The solution was diluted with 1N HCl and extracted with DCM (twice). The combined organic phases were washed with brine and dried over ו4. Filtration and concentration gave 3.89 g (81% yield) of formylated glycine as an oil (M + 1 = 194).

Triethylamine (3.2 mL, 23 mmol) was added to a solution of the formylated glycine derivative (1 g, 5.2 mmol) in DCM (30 mL). The solution was cooled to −50 ° C. and POCl ₃ (1.9 mL, 20.8 mmol) was added slowly. The solution was stirred at −50 C for 10 minutes and then at room temperature for 40 minutes. The solution exhibited a pale reddish brown color. It was diluted with DCM and a 20% sodium carbonate solution (100 mL) was added. The reaction mixture was vigorously stirred for 15 minutes. The organic phase was separated twice and dried over 00544. By filtering and concentrating, the desired benzyl isocyanocyanoacetate was obtained in quantitative yield and used in the next step without further purification.

_{I-Pr 2} NEt (2.5 mL, 14.6 mmol) was added to a solution of 1,2,4-triazole (914 mg, 13.2 mmol) in _{anhydrous CH 3} CN (20 mL) at 0 ° C. Once all triazoles were dissolved, POCl ₃ (0.43 mL, 4.6 mmol) was added. The mixture was stirred at 0 ° C. for 2 hours. Lactam ester 16'(1 g, 3.31 mmol) was added. The resulting solution was heated in an oil bath at 80 ° C. for 16 hours. The mixture was cooled using an ice bath. Dilute with EtOAc and then add water. The aqueous layer was separated and extracted 4 times with EtOAc. The combined organic extracts were washed with brine, dried over MgSO _4. Filtration and concentration gave a pale yellow solid which was used as is in the next step (M + 1 = 354).

A solution of benzyl isocyanoacetate (892 mg, 5.1 mmol) in DMF (10 mL) was cooled to −50 ° C. under a nitrogen atmosphere. KOtBu (514 mg, 4.6 mmol) was added. The mixture was stirred at −50 ° C. for 1 hour. The triazole derivative (900 mg, 2.55 mmol) prepared above in DMF (5 mL) was added slowly at −50 ° C. The mixture was warmed to room temperature for 16 hours. The addition of saturated aqueous _NH 4 Cl and it was extracted 3 times with EtOAc. The combined extracts were washed with brine (3 times) and dried with _ו4. Crude products were obtained by filtration and concentration. Chromatography (RediSep 24 g silica-gel column, eluted with 70% EtOAc in hexanes) gave 886 mg (76% yield) of product (M + 1 = 460).

Wet Pd / C (60 mg) was added to a solution of the benzyl ester derivative (770 mg, 1.68 mmol) in EtOAc (10 mL) and MeOH (30 mL) and the resulting suspension was stirred under a hydrogen atmosphere for 48 hours. did. The suspension was filtered through Celite and the resulting solution was concentrated. The debenzylated crude product (530 mg, 86% yield) was used in the next step without further purification (M + 1 = 370).

CDI (931 mg, 5.75 mmol) was added to the suspension of acid (530 mg, 1.44 mmol) in DCM (10 mL). The solution was stirred at room temperature for 2 hours. The solution was cooled using an ice bath and NH ₄ OH solution (6 mL) was added. The solution was stirred for 30 minutes and concentrated. The solid was collected by filtration and washed with water to give 422 mg (80%) of the desired product as a brown solid (M + 1 = 369).

_{POCl 3} (160 μL, 1.7 mmol) was added to the suspension of the primary amide derivative (422 mg, 1.15 mmol) in dioxane (10 mL). The suspension was heated at 90 ° C. for 2 hours. The resulting solution was cooled using an ice bath and quenched with _{saturated aqueous NaHCO 3 solution.} The solid was recovered by filtration to give 308 mg (77% yield) of the desired cyanide derivative (M + 1 = 351).

Hydroxylamine hydrochloride (40 mg, 0.57 mmol) and potassium carbonate (67 mg, 0.48 mmol) were added to the suspension of cyanide derivative (150 mg, 0.44 mmol) in EtOH (4 mL) and water (1 mL). .. The suspension was stirred at room temperature for 16 hours. LCMS showed a conversion of about 50%. Further hydroxylamine hydrochloride (40 mg, 0.57 mmol) and potassium carbonate (67 mg, 0.48 mmol) were added, and the mixture was further stirred for 24 hours. The solution was diluted with EtOAc and washed with water. The combined organic phases were washed with brine, dried over MgSO _4. Filtration and concentration gave 145 mg (86% yield) of the desired product (M + 1 = 384).

CDI (123 mg, 0.76 mmol) was added to a solution of acetic acid (0.22 mL, 3.8 mmol) in THF (5 mL). The solution was stirred at room temperature for 2 hours. The solution was then poured into a flask containing the oxime derivative (145 mg, 0.38 mmol) and heated at 70 C for 1 hour. The solvent was evaporated, the crude material was suspended in acetic acid (8 mL) and heated at 130 ° C. for 1 hour. The solvent was evaporated and the crude material was ground with water to give 134 mg (86%) of the desired product (M + 1 = 408).

Lithium aluminum hydride (7 mg, 0.18 mmol) was added to the suspension of the ester derivative (50 mg, 0.12 mmol) in THF (1 mL). The suspension was stirred at room temperature for 2 hours. LCMS showed about 70% conversion, along with some other by-products and some residual starting material. Further lithium aluminum hydride (4 mg) was added and the reaction mixture was stirred at room temperature for an additional 30 minutes. The reaction mixture was quenched with 1N HCl. The solution was extracted with EtOAc (3 times). The combined organic phases were washed with brine, dried over MgSO _4. Filtration and concentration gave 20 mg (45% yield) of the desired alcohol product (M + 1 = 366).

_{POBr 3} (31 mg, 0.11 mmol) was added to the suspension of alcohol (20 mg, 0.055 mmol) in dioxane (1 mL). The reaction mixture was heated at 110 ° C. for 1 hour. The reaction mixture was cooled using an ice bath and saturated _{aqueous NaHCO 3} solution was added. The resulting solution was extracted with EtOAc (3 times). The combined organic phases were washed with brine, dried over MgSO _4. Concentration of the solvent gave 22 mg (96% yield) of the desired product (M + 1 = 428).

中間体Ａ（エチル１５−クロロ−９−（メトキシメチル）−２，４，８，１０，１１−ペンタ−アザテトラシクロ［１１．４．０．０^２，^６．０^８，^１２］ヘプタデカ−１（１７），３，５，９，１１，１３，１５−ヘプタエン−５−カルボキシレート）の合成。 To a vial containing an alkyl bromide derivative (22 mg, 0.052 mmol) was added 3-fluorophenol (58 mg, 0.52 mmol) and potassium carbonate (72 mg, 0.52 mmol) in dioxane (1 mL). The reaction mixture was heated at 90 ° C. for 1 hour. The reaction mixture was diluted with _{saturated aqueous NaHCO 3 solution.} The resulting solution was extracted with EtOac (3 times). The combined organic phases were washed with brine, dried over MgSO _4. Crude products were obtained by filtration and concentration. Purification by preparative TLC (eluting system: EtOAc) gave 5 mg (21% yield) of the desired product compound 168 (M + 1 = 460). H ¹ NMR (CDCl ₃ ) δ7.87 (1H, s), 7.65 (1H, d, J = 3.5Hz), 7.57 (1H, d, J = 10Hz), 7.24 (1H, m), 7.19 (1H, dd, J = 3.5, 9Hz), 6.77 (1H, dd, J = 2.5, 9.5Hz), 6.72 (2H, m), 5.26 (2H, s), 3.97 (3H, s), 2.48 (3H, s) ..
Synthesis scheme 28 of compounds 215-313

Intermediate A (ethyl 15-chloro-9- (methoxymethyl) -2,4,8,10,11- penta - aza tetracyclo ^{[11.4.0.0 2, 6 .0 8,} 12] heptadeca - 1 (17), 3,5,9,11,13,15-Heptaene-5-carboxylate) synthesis.

A solution of ethyl bromoacetate (Scheme 28) (10.0 g, 59.87 mmol) in 20.0 mL anhydrous THF, (2,4-dimethoxybenzyl) amine (10.0 g, 59.81 mmol) and triethylamine (6. It was added dropwise to a solution in anhydrous THF (20.0 mL) of 06 g, 59.87 mmol) at 0 ° C. under a nitrogen atmosphere. The reaction mixture was warmed to room temperature and stirred overnight. About 100 mL of brine was added and the reaction mixture was extracted with ethyl acetate (2 x about 100 mL). The combined extracts were dried over anhydrous י ₄ and concentrated under reduced pressure. Purification was performed using combiFlash chromatography (gradient: 20:80-50: 50v / v ethyl acetate: hexane). An alkylation product of 7.6 g (yield 50.2%) was obtained as a colorless liquid. m / z calculated for C ₁₃ H ₁₉ NO ₄ [M + H] ⁺ : 254; Obtained: 254.1.
This ester (7.5 g, 29.6 mmol) was dissolved in 40.0 mL of methanol. The reaction mixture was cooled and a 2N aqueous NaOH solution (88.82 mmol, 44.0 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with about 75.0 mL of water, cooled in an ice bath and neutralized to a pH of about 5.0-4.5 using 2N aqueous HCl. Excess water was concentrated under reduced pressure and air was allowed to flow to give a white solid powder. The solid was dissolved in 85: 15 v / v DCM: MeOH (100.0 mL) and filtered and the filtrate was evaporated to give 7.1 g of carboxylic acid as a white powder (hygroscopic). m / z calculated for C ₁₁ H ₁₅ NO ₄ [M + Na] ⁺ : 248; Obtained: 248.1.

The above compounds (7.0 g, 31.08 mmol) and 6.14 g, 31.08 mmol of 5-chloroisatoic acid anhydride were mixed in 70.0 mL of p-xylene and refluxed at a temperature of 140 ° C. for 3 hours. .. The reaction mixture was filtered and the crude product was recrystallized from methanol. Obtaining 8.5 g of 7-chloro-4-[(2,4-dimethoxyphenyl) methyl] -2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2,5-dione as a white powder (Yield of 75.8%). m / z calculated for C ₁₈ H ₁₇ ClN ₂ O ₄ [M + H] ⁺ : 361; Obtained: 361.1.

The benzodiazepine-2,5-dione (4 g, 11.1 mmol) was dissolved in THF / DMF (57.2 / 12.7 mL) and cooled to a temperature of −20 ° C. Finely divided potassium-tert-butoxide powder (1.9 g, 16.6 mmol) was added and the reaction mixture was stirred at −20 ° C. for 20.0 minutes. 3.1 g, 17.7 mmol of diethylchlorophosphate was added dropwise to the reaction mixture at −20 ° C. to 0-5 ° C. in 3 hours. The reaction mixture was stirred at ambient temperature for 10.0 minutes. 2.1 g, 18.4 mmol of ethyl acetate, was added to the reaction mixture at −20 ° C. and the reaction mixture was further cooled to −78 ° C. 1.9 g, 16.6 mmol of finely divided potassium-tert-butoxide powder was added at −78 ° C. and the reaction mixture was stirred overnight by slowly warming to ambient temperature. The reaction mixture was quenched with saturated aqueous _NH 4 Cl (10 mL), and extracted with ethyl acetate (3 × 20mL). The combined extracts were dried over anhydrous י ₄ and concentrated under reduced pressure. This crude product is recrystallized from ethyl acetate and 2.2 g of ethyl 12-chloro-8-[(2,4-dimethoxyphenyl) methyl] -9-oxo-2,4,8-triazatricyclo. [8.4.0.0 ² , ⁶ ] Tetradeca-1 (14), 3,5,10,12-pentaene-5-carboxylate was obtained as a white solid. A second collection was obtained from the mother liquor to give an additional 3.5 g of product (64% yield).

The dimethoxybenzyl protecting group is dissolved in DCM (25.0 mL) of the above compound (2.2 g, 4.83 mmol), followed by 25.0 mL of trifluoroacetic acid and 1.45 g, 9.65 mmol of trifluomethanesulfonate. It was removed by adding acid. The reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture _{was neutralized with aqueous NaHCO 3} solution, and the precipitate was filtered, washed with water and dried to dryness with 1.9 g of ethyl 12-chloro-9-oxo-2,4,8-tria. The tricyclo [8.4.0.0 ² , ⁶ ] tetradeca-1 (14), 3, 5, 10, 12-pentaene-5-carboxylate was obtained as a solid product. m / z calculated for C ₁₄ H ₁₂ ClN ₃ O ₃ [M + H] ⁺ : 306; Obtained: 306.1.

In the first step, ethyl 12-chloro-9-oxo-2,4,8-triazatricyclo [8.4.0.0 ² , ⁶ ] tetradeca-1 (14), 3, 5 from the above. , 10,12-Pentaene-5-carboxylate (1.9 g, 6.21 mmol) was dissolved in 25.0 mL of chlorobenzene, followed by 2.52 g, 18.64 mmol of 4,N, N-trimethylaniline, 1 .42 g, 9.32 mmol of POCl ₃ was added and the reaction mixture was refluxed at 135 ° C. for 2 hours. LCMS shows that about 50% of the starting material remains unreacted. 1.68 g, 12.42 mmol of additional 4,N, N-trimethylaniline and 0.95 g, 6.21 mmol of POCl ₃ were further added to the reaction mixture at room temperature and refluxed at 135 ° C. for 1 hour. LCMS shows that about 10% of the starting material remains unreacted. Further 0.84 g, 6.21 mmol of 4,N, N-trimethylaniline (total 6.0 _{eq.) And 0.48 g, 3.11 mmol of POCl 3} (total 3 eq.) Were added to the reaction mixture at room temperature. And refluxed at 135 ° C. for 1 hour.

In the second step, 4.67 g, 44.75 mmol of methoxyacetic acid hydrazide (total 7.2 eq.), Followed by 7.71 g, 59.66 mmol of N, N-diisopropylethylamine was added to the reaction mixture at room temperature. And refluxed at 100 ° C. for 1 hour. The reaction mixture was cooled to room temperature _{and neutralized with aqueous NaHCO 3} solution (approximately 25.0 mL). The organic matter was extracted with ethyl acetate (75 mL x 3), then with DCM (50.0 mL x 3) and washed with brine. The EtOAc organic layer, the insoluble precipitate is separated by filtration (pure product 0.805 g), and the combined organic layers were dried over anhydrous MgSO _4, and concentrated under reduced pressure. The crude product was purified by Combiflash chromatography (mobile phase: 0-10% MeOH: EtOAc) to give an additional 0.8 g of yellow solid. Intermediate A (ethyl 15-chloro-9- (methoxymethyl) -2,4,8,10,11- pentaaza tetracyclo [11.4.0.0 ² for the last two steps, ^{6.0 8} , ¹² ] -Heptadeca-1 (17), 3,5,9,11,13,15-Heptaene-5-carboxylate) total yield was 72.58%. m / z calculated for C ₁₇ H ₁₆ ClN ₅ O ₃ [M + H] ⁺ : 374; Obtained: 374.1.
Intermediate B (15-chloro-9- (methoxymethyl) -2,4,8,10,11- penta - aza tetracyclo ^{[11.4.0.0 2, 6 .0 8,} 12] heptadeca -1 (17), 3,5,9,11,13,15-heptaene-5-carboxylic acid) synthesis.

化合物２３３の合成：

Intermediate A (0.4 g, 1.07 mmol _{) was dissolved in a mixture of THF / H 2} O / MeOH (3.2 / 4.8 / 8.0 v / v mL). 0.05 g, 2.14 mmol of LiOH was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified with 2N aqueous HCl, the precipitate was collected and washed with deionized water. After drying, Intermediate B (15-chloro-9- (methoxymethyl 0.36g) -2,4,8,10,11- penta - aza tetracyclo [11.4.0.0 ^{2, 6} .0 ⁸ , ¹² ] Heptadeca-1 (17), 3,5,9,11,13,15-Heptaene-5-carboxylic acid) was obtained as a white solid. m / z calculated for C ₁₅ H ₁₂ ClN ₅ O ₃ [M + H] ⁺ : 346; Obtained: 345.9.
Scheme 29 illustrates some selected examples of using Intermediate A to generate new analogs.
Scheme 29

Synthesis of compound 233:

Acetone oxime (0.22 g, 0.31 mmol) was dissolved in anhydrous THF (0.5 mL). 0.38 mL, 0.62 mmol of 1.6 M n-BuLi was added dropwise and the reaction mixture was stirred in another flask at 0-5 ° C. for 1 hour. A solution of Intermediate A (0.05 g, 0.13 mmol) in 1.0 mL THF was added by cannula at 0-5 ° C. and the reaction was stirred for 16 hours by gradually warming to room temperature. .. LCMS showed starting material and intermediate m / z: 374.1 (about 45/14%, two combined peaks), m / z 401 (about 10%), m / z 402 (18%). rice field.

The reaction mixture was quenched with 0.03 mL of concentrated H ₂ SO ₄ , then quenched with 0.03 mL of deionized water and refluxed for 2 hours. LCMS showed m / z: 374.1 (about 43%), m / z 383 (about 40%), m / z 402 (17%) for starting materials, products and intermediates.

The reaction mixture was concentrated under reduced pressure _{and neutralized with aqueous NaHCO 3} solution, the precipitate was collected and washed with deionized water. After drying, 22.0 mg of crude precipitate was obtained. Compounds were purified by prep-TLC plate using 1:99 MeOH: CHCl _3.
Synthesis of compound 238:

Step: 1 Intermediate A (0.045 g, 0.12 mmol) was dissolved in anhydrous toluene (3.0 mL). 0.05 mL, 0.25 mmol of aminoethanol (35.0 eq) was added and the reaction mixture was refluxed for 16 hours. The toluene was evaporated and the reaction mixture was dissolved in DCM (25.0 mL). The DCM layer was washed with brine, then with deionized water, separated and dried over anhydrous ו ₄ . Evaporation of the organic layer gave 38.3 mg of the corresponding amide. LCMS showed m / z: 389 of product formation.

Step: 2 The above amide (0.038 g, 0.09 mmol) was dissolved in dry DCM (2.0 mL). 0.026 mL, 0.2 mmol DAST (2.0 eq) was added to the reaction mixture at a temperature of 0 ° C. and stirred at 0 ° C. for 1.5 hours. 0.065 g of solid K ₂ CO ₃ (4.8 eq) was added at 0 ° C. and the reaction mixture was stirred for 30 minutes. The reaction mixture _{was diluted with 3} aqueous NaHCO and extracted with DCM (15.0 mL x 3). The organic layer was washed with brine, separated and dried over anhydrous י ₄ . Evaporation of the solvent gave 36 mg of white solid product. m / z calculated for C ₁₇ H ₁₅ ClN ₆ O ₂ [M + H] ⁺ : 371; Obtained: 371.
Synthesis of compound 239:

Step: 1 Intermediate A (0.05 g, 0.13 mmol) was dissolved in anhydrous toluene (3.0 mL). 0.28 g, 2.67 mmol of aminoethanol (20.0 eq) was added and the reaction mixture was refluxed for 16 hours. The toluene was evaporated and the reaction mixture was dissolved in DCM (25.0 mL). The DCM layer was washed with brine, then with deionized water, separated and dried over anhydrous י ₄ . The amide was obtained by evaporation of the organic layer. LCMS showed m / z: 431 of product formation.

Step: 2 The above amide (0.057 g, 0.13 mmol) was dissolved in dry DCM (2.0 mL). 0.035 mL, 0.3 mmol DAST (2.0 eq) was added to the reaction mixture at a temperature of 0 ° C. and stirred at 0 ° C. for 1.5 hours. LCMS showed m / z 413 of product formation. 0.088 g of solid K ₂ CO ₃ (4.8 eq) was added at 0 ° C. and the reaction mixture was stirred for 30 minutes. The reaction mixture _{was diluted with 3} aqueous NaHCO and extracted with DCM (15.0 mL x 3). The organic layer was washed with brine, separated and dried over anhydrous י ₄ . The product was obtained by concentration of the organic layer, which was ground with 20/80 Hex / EtOAc to give a solid, which was collected by filtration and dried: 49.4 mg (89%).
Synthesis of compound 243:

Step: 1 Intermediate A (0.05 g, 0.13 mmol) was dissolved in anhydrous toluene (3.0 mL). 0.02 mL, 2.67 mmol of amino alcohol (20.0 eq) was added and the reaction mixture was refluxed for 16 hours. LCMS showed that the starting material remained. Xylene was added (3.0 mL), 10.0 eq of 3-aminobutane-1-ol was added, and the reaction mixture was refluxed for 16 hours. A total of 40.0 eq of aminoethanol was ultimately required to convert all starting material to product in refluxed xylene. The reaction mixture was cooled to 0 ° C. and the precipitate was filtered. The filtrate was extracted with DCM (15.0 mL x 4). The DCM layer was washed with brine, then with deionized water, separated and dried over anhydrous י ₄ . Evaporation of the organic layer gave the corresponding amide. LCMS showed m / z: 403 of product formation.

Step: 2 The above amide (0.054 g, 0.13 mmol) was dissolved in dry DCM (2.0 mL). 0.05 mL, 0.33 mmol of DAST was added to the reaction mixture at a temperature of 0 ° C. and stirred at 0 ° C. for 1.5 hours. LCMS showed product formation. 0.09 g of solid K ₂ CO ₃ was added at 0 ° C. and the reaction mixture was gradually warmed to room temperature. The reaction mixture _{was diluted with 3} aqueous NaHCO and extracted with DCM (15.0 mL x 3). The organic layer was washed with brine, separated and dried over anhydrous י ₄ . The crude product was obtained by evaporation of the solvent. Purification was performed by prep TLC (mobile phase: 95:05 DCM: MeOH). m / z calculated for C ₁₈ H ₁₇ ClN ₆ O ₂ [M + H] ⁺ : 385; Obtained: 385.
Synthesis of compound 244:

Compound 243 (0.011 g, 0.03 mmol) from the above was dissolved in toluene (2.0 mL). 0.010 g, 0.04 mmol of DDQ was added and the reaction mixture was stirred at 50 ° C. for 1 hour. LCMS showed m / z 385 as a starting material and m / z 383 as a small amount of product. The reaction mixture was stirred at 60 ° C. for 3 hours. LCMS showed m / z 385 for the starting material and m / z 383 for the product. The reaction mixture was stirred at 70 ° C. for 2 hours. LCMS showed the starting material m / z 385, the product m / z 383, and the by-product m / z 421. The reaction mixture was stirred at 40 ° C. for 16 hours. LCMS showed a large amount of product m / z 383 and a small amount of by-product m / z 421 and starting material. The toluene was evaporated and the crude product was purified by a prep-TLC plate (mobile phase DCM: MeOH, 95: 05v / v) to give 4.4 mg of product. m / z calculated for C ₁₈ H ₁₅ ClN ₆ O ₂ [M + H] ⁺ : 383; Obtained: 383.
Synthesis of compound 249:

Compound 238 (0.016 g, 0.05 mmol) from the above was dissolved in toluene (2.0 mL). 0.015 g, 0.07 mmol of DDQ was added and the reaction mixture was stirred at 50 ° C. for 1 hour. LCMS showed a starting material of m / z 371. The reaction mixture was stirred at 60 ° C. for 5 hours. LCMS showed m / z 371 of starting material, m / z 369 of product and undesired m / z 407. The reaction mixture was stirred at 30 ° C. for 16 hours. LCMS showed the starting material m / z 371, the product m / z 369 and the by-product m / z 407. The reaction mixture was stirred at 65 ° C. for 4 hours. LCMS showed product m / z 369, by-product m / z 407, and small amounts of starting material. The toluene was evaporated and the crude product was purified by a prep-TLC plate (mobile phase DCM: MeOH, 95: 05v / v) to give 2.3 mg of product. m / z calculated for C ₁₇ H ₁₃ ClN ₆ O ₂ [M + H] ⁺ : 369; Obtained: 369.
Synthesis of compound 256:

Step 1: Intermediate A (0.1 g, 0.27 mmol) was dissolved in anhydrous THF (3.0 mL). A solution of 0.67 mL, 0.67 mmol of DIBAL in THF, 1.0 M was added dropwise and the reaction mixture was stirred at 0-5 ° C. for 2 hours. LCMS shows m / z 332 of the formation of alcohol reduction products. This reaction was quenched with MeOH (1.0 mL) and then with water (0.5 mL). A saturated solution of NaHCO ₃ was added and the precipitate was filtered through a Celite pad. This product was extracted using DCM (25.0 mL x 3). The combined DCM layers were washed with brine, separated and dried over anhydrous Na ₂ SO ₄ . Evaporation of the solvent, [15-chloro-9- (methoxymethyl) of 46.1 mg -2,4,8,10,11- pentaaza tetracyclo [11.4.0.0 ^{2, 6.} 0 ^{8, 12]} heptadeca-1 (17), the 3,5,9,11,13,15- heptaene-5-yl] methanol as a solid product, was obtained 51.9% yield. m / z calculated for C ₁₅ H ₁₄ ClN ₅ O ₂ [M + H] ⁺ : 332; Obtained: 332.

Step 2: The above alcohol (0.05 g, 0.14 mmol) was dissolved in anhydrous DCM (3.0 mL). 0.09 g of Dess-Martin peryodinane was added and the reaction mixture was stirred at room temperature for 2 hours. LCMS shows m / z 330 of product formation. This reaction was quenched with 1N NaOH solution (2 mL). A saturated solution of NaHCO ₃ was added and the product was extracted using DCM (20.0 mL × 3). The combined DCM layers were washed with brine, separated and dried over anhydrous Na ₂ SO ₄ . Evaporation of the solvent, the desired aldehyde (15-chloro-9- (methoxymethyl) -2,4,8,10,11- pentaaza tetracyclo [11.4.0.0 ^{2, 6} .0 ^{8, 12} ] Heptadeca-1 (17), 3,5,9,11,13,15-heptaene-5-carbaldehyde) was obtained as a solid product in a quantitative yield. m / z calculated for C ₁₅ H ₁₂ ClN ₅ O ₂ [M + H] ⁺ : 330; Obtained: 330.

Step 3: A 1.6 M solution of n-BuLi (0.68 mL, 1.08 mmol) in hexane was dissolved in 3.0 mL of THF into a 1.4 mL, 0.86 mmol trimethylsilyldiazomethane solution in hexane. It was added by dropping at a temperature of −78 ° C. The reaction mixture was stirred at a temperature of −78 ° C. for 30.0 minutes. A solution of the aldehyde (0.142 g, 0.43 mmol) obtained in step 2 in 3.0 mL THF was added dropwise to the reaction mixture at a temperature of −78 ° C. and gradually warmed to room temperature. LCMS shows m / z 326 of product formation and m / z 330 of starting material. The reaction mixture was quenched with _{saturated NH 4 Cl solution.} This product was extracted using DCM (15.0 mL x 3). The combined DCM layers were washed with brine, separated and dried over anhydrous Na ₂ SO ₄ . Purification of the crude product was performed by the ISCO Combiflash purification system (mobile phase: ethyl acetate / hexane). 19.0 mg of compound 256 was obtained and 71.6 mg of starting material was isolated. m / z calculated for C ₁₆ H ₁₂ ClN ₅ O [M + H] ⁺ : 326; Obtained: 326.
Synthesis of compound 285:

Compound 256 (0.025 g, 0.08 mmol) was dissolved in degassed DMF (2.0 mL). 0.03 mL, 0.23 mmol of iodobenzene was added to this reaction mixture, followed by 0.06 mL, 0.41 mmol of TEA. The reaction mixture was stirred at room temperature. A mixture of 0.04 g, 0.04 mmol of Pd (PPh ₃ ) ₄ and 0.003 g, 0.015 mmol of CuI was added to the reaction mixture and stirred for 16 hours. LCMS shows m / z 402 of product formation. The reaction mixture was diluted with deionized water. This product was extracted using DCM (10.0 mL x 3). The combined DCM layers were washed with brine, separated and dried over anhydrous Na ₂ SO ₄ . The crude reaction mixture was purified on a prep-TLC plate (mobile phase: EtOAc / MeOH). m / z calculated for C ₂₂ H ₁₆ ClN ₅ O [M + H] ⁺ : 402; Obtained: 402.
Synthesis of compound 254:

Isobutyronitrile (10.0 g, 144.70 mmol) is dissolved in EtOH: water (150: 50 mL, v / v), followed by 10.0 g, 144.70 mmol of hydroxylamine hydrochloride and 20.0 g, 144. .70 mmol of K ₂ CO ₃ was added. The reaction mixture was refluxed at 80 ° C. for 6 hours. The solvent was evaporated under reduced pressure and the resulting solid was treated with 150 mL ethanol, sonicated, filtered and washed with 100 mL ethanol. The combined filtrate was evaporated under reduced pressure and azeotroped with toluene (25.0 mL x 3) to give 8.1 g of N'-hydroxy-2-methylpropmidamide as a colorless liquid slurry (54. 8% yield). The amide-oxime (1.37 g, 13.38 mmol) was azeotroped with toluene (10 mL × 5) prior to use and dissolved in 20.0 mL anhydrous THF. 0.27 g, 6.69 mmol of NaH was added to the reaction mixture in 3 portions at 0 ° C. and stirred at ambient temperature for 30.0 minutes. 0.5 g, 1.34 mmol of Intermediate A was added, and the reaction mixture was stirred at ambient temperature for 45.0 minutes and refluxed at 67 ° C. for 90.0 minutes. The solvent was evaporated under reduced pressure and the resulting yellow paste was treated with 25.0 mL saturated _{aqueous NaHCO 3} solution. The precipitate was filtered through a funnel and washed with 10.0 mL of water and 10.0 mL of hexane to give 0.380 g of solid (69.1% yield). m / z calculated for C ₁₉ H ₁₈ ClN ₇ O ₂ [M + H] ⁺ : 412.0; Obtained: 412.1.
Synthesis of compound 215

This alcohol [15-chloro-9- (methoxymethyl) -2,4,8,10,11-pentaazatetracyclo [11.4.0.0 ² , ⁶ . 0 ^{8, 12]} heptadeca-1 (17), 3,5,9,11,13,15- heptaene-5-yl] methanol (Compound 256, prepared in Step 1) (34mg, 0.1025mmol) and dried Suspended in THF (2 mL). After adding HMPA (36.7 mg, 0.205 mmol), ethyl iodide (0.33 mL) and NaH (41 mg 60% suspension in oil) were added. The reaction was stirred at room temperature for 5 minutes and then heated to 70 ° C. overnight. The mixture was cooled and partitioned between EtOAc and brine. The organic phase was dried and concentrated to give an oil, which was purified by column chromatography (0% -10% MeOH in DCM) to give 3.7 mg of compound 215 as an oil.
Synthesis of compound 274

化合物２３４の合成：

[15-chloro-9- (methoxymethyl) -2,4,8,10,11 pentaaza tetracyclo [11.4.0.0 ^{2, 6.} 0 ^{8, 12]} heptadeca-1 (17), 3,5,9,11,13,15- heptaene-5-yl] dissolved in methanol (0.02 g, 0.06 mmol) in anhydrous THF (3.0 mL) I let you. 0.003 g of NaH was added and the reaction mixture was stirred at room temperature for 30.0 minutes. 0.012 mL, 0.12 mmol of 2-bromopyridine was added dropwise and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was refluxed for an additional 2 hours. LCMS indicates m / z 409. The reaction was concentrated under reduced pressure and diluted with a saturated solution of _{NaHCO 3.} This product was extracted using DCM (10.0 mL x 4). The combined DCM layers were washed with brine, separated and dried over anhydrous Na ₂ SO ₄ . Purification was performed by prep TLC (mobile phase: 95:05 DCM: MeOH). About 1.0 mg of product was obtained. m / z calculated for C ₂₀ H ₁₇ ClN ₆ O ₂ [M + H] ⁺ : 409; Obtained: 409.
Scheme 30 illustrates some selected examples of using Intermediate B to generate new analogs.
Scheme 30

Synthesis of compound 234:

Intermediate B (0.043 g, 0.12 mmol), 0.3 mmol EDC. HCl and 0.048 g, 0.31 mmol of HOBt hydrate are dissolved in THF / DCM (1: 1, v / v 1.5 mL), followed by 0.09 mL, 0.62 mmol of trimethylaniline and 0. 016 mL, 0.25 mmol of propargylamine was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with aqueous ammonium chloride solution and extracted with ethyl acetate. The combined layers were washed with brine, separated and dried over anhydrous י ₄ . Evaporation of the organic layer gave about 13.0 mg of crude product. The crude product was purified by preparative TLC plate (mobile phase: 5:95 MeOH, ethyl acetate). m / z calculated for C ₁₈ H ₁₅ ClN ₆ O ₃ [M + H] ⁺ : 383; Obtained: 383.1.
Synthesis of compound 240:

Step 1 Intermediate B (0.05 g, 0.15 mmol) was dissolved in dry DCM (2.0 mL). After adding 0.05 mL, 0.36 mmol of trimethylamine (2.5 eq), 0.024 mL, 0.29 mmol of oxalyl chloride (2.0 eq) was added, and the reaction mixture was stirred at room temperature for 60 minutes. 0.076 mL, 0.7 mmol amino-alcohol (5.0 eq) was added to the reaction mixture at 0 ° C. and the reaction mixture was diluted with an aqueous solution of _{NaHCO 3 for 2.5 hours and DCM (15.0 mL).} Extracted in × 3). The combined organic layers were washed with brine, separated and dried over anhydrous י ₄ . Evaporation of the organic layer gave 54.1 mg of amide. LCMS showed m / z: 431 of product formation.

Step 2 (2S) -2-Amino-3-methylbutyl 15-chloro-9- (methoxymethyl) -2,4,8,10,11-pentaazatetracyclo [11.4.0.0 ² , ⁶ . 0 ^{8, 12]} heptadeca-1 (17), 3,5,9,11,13,15- heptaene-5-carboxylate (0.027 g, 0.06 mmol) dissolved in dry DCM (2.0 mL) rice field. 0.016 mL, 0.13 mmol DAST was added to the reaction mixture at a temperature of 0 ° C. and stirred at 0-5 ° C. for 3 hours. LCMS showed product formation. 0.04 g of solid K ₂ CO ₃ was added at 0 ° C. and the reaction mixture was gradually warmed to room temperature. The reaction mixture _{was diluted with aqueous NaHCO 3} aqueous solution and extracted with DCM (15.0 mL x 3). The organic layer was washed with brine, separated and dried over anhydrous י ₄ . The crude product was obtained by evaporation of the solvent. Purification was performed by prep TLC (mobile phase: 95:05 DCM: MeOH). 23.7 mg of solid product was obtained. Mass m / z calculated for C ₂₀ H ₂₁ ClN ₆ O ₂ [M + H] ⁺ : 413; Obtained: 413.
Synthesis of compound 246:

Compound 240 was converted to compound 246 at 50C using DDQ, toluene in a manner similar to compound 245 to give 5.5 mg (37%) of compound 246. LCMS showed m / z: 411 for product formation.
Synthesis of compound 242:

Step 1: Intermediate B (0.025 g, 0.07 mmol) was dissolved in dry DCM (2.0 mL). After adding 0.03 mL, 0.21 mmol of trimethylamine (3.0 eq), 0.015 mL, 0.18 mmol of oxalyl chloride (2.5 eq) was added, and the reaction mixture was stirred at room temperature for 60 minutes. 0.05 g, 0.36 mmol of (R, S) -2-amino-2-phenylethane-1-ol (5.0 eq) was added to this reaction mixture at 0 ° C. and stirred at room temperature for 2.5 hours. did. The reaction mixture _{was diluted with aqueous NaHCO 3} and extracted with DCM (15.0 mL x 3). The combined organic layers were washed with brine, separated and dried over anhydrous י ₄ . The desired amide was obtained by evaporation of the organic layer. LCMS showed m / z: 465 of product formation.

Step 2: The above amide (0.034 g, 0.07 mmol) was dissolved in dry DCM (2.0 mL). 0.03 mL, 0.22 mmol DAST was added to the reaction mixture at a temperature of 0 ° C. and stirred at 0 ° C. for 1.5 hours. LCMS showed product formation. 0.05 g of solid K ₂ CO ₃ was added at 0 ° C. and the reaction mixture was gradually warmed to room temperature. The reaction mixture _{was diluted with 3} aqueous NaHCO and extracted with DCM (15.0 mL x 3). The organic layer was washed with brine, separated and dried over anhydrous י ₄ . The crude product was obtained by evaporation of the solvent. Purification was performed by prep TLC (mobile phase: 95:05 DCM: MeOH). m / z calculated for C ₂₃ H ₁₉ ClN ₆ O ₂ [M + H] ⁺ : 447; Obtained: 447.
Synthesis of compound 245:

Compound 242 (0.015 g, 0.03 mmol) was dissolved in toluene (1.5 mL). 0.009 g, 0.04 mmol of DDQ was added and the reaction mixture was stirred at 50 ° C. for 1.5 hours. LCMS showed the starting material m / z 447 and the product m / z 445 in a 1: 3 ratio. 0.005 g, 0.022 mmol of DDQ was further added and the reaction mixture was stirred at 50 ° C. for 1.5 hours. The starting material m / z 447 and the product m / z 445 in a ratio of 1: 6. The reaction mixture was stirred at room temperature for 16 hours. Purification was performed by prep TLC (mobile phase: 95:05 DCM: MeOH). A band with m / z: 445 was isolated and 9.3 mg of solid compound was obtained (yield 62.4%). m / z calculated for C ₂₃ H ₁₇ ClN ₆ O ₂ [M + H] ⁺ : 445; Obtained: 445.
Synthesis of compound 237:

Step 1: Intermediate B (0.025 g, 0.07 mmol) was dissolved in dry DCM. After adding 0.009 mL, 0.02 mL, 0.14 mmol of trimethylamine, 0.11 mmol of oxalyl chloride was added, and the reaction mixture was stirred at room temperature for 30 minutes. 0.028 mL, 0.36 mmol of 3-amino-1-propanol was added to the reaction mixture at 0 ° C., and the mixture was stirred for 2.5 hours and then concentrated. LCMS showed m / z: 403 of product formation, leaving a small amount of starting material.

Step 2: The crude amide from Step 1 (0.018 g, 0.045 mmol) was dissolved in dry DCM (2.0 mL). 0.012 mL, 0.09 mmol DAST was added to the reaction mixture at a temperature of −78 ° C. and gradually warmed to 0 ° C. 0.03 g of solid K ₂ CO ₃ was added at −78 ° C. and the reaction mixture was gradually warmed to room temperature. The reaction mixture _{was diluted with 3} aqueous NaHCO and extracted with DCM (15.0 mL x 3). The organic layer was washed with brine, separated and dried over anhydrous י ₄ . Evaporation of the solvent gave 14.7 mg of compound 237 as a white solid product. m / z calculated for C ₁₈ H ₁₇ ClN ₆ O ₂ [M + H] ⁺ : 385; Obtained: 385.1.
Synthesis of compound 263:

Step 1: Intermediate B (0.03 g, 0.09 mmol), 0.034 g, 0.17 mmol EDC. HCl and 0.027 g, 0.17 mmol HOBt. xH ₂ O was dissolved in anhydrous DCM (2.5 mL). 0.024 g, 0.17 mmol R- (-)-2-phenylglycinol was added and the reaction mixture was stirred at room temperature for 6 hours. LCMS showed m / z 464.9 of product formation. The reaction mixture was diluted with deionized water and extracted with DCM (10.0 mL x 3). The combined DCM layers were washed with brine, separated and dried over anhydrous Na ₂ SO ₄ . The crude product was obtained by evaporation of the organic layer. A liquid syrup was obtained. m / z calculated for C ₂₃ H ₂₁ ClN ₆ O ₃ [M + H] ⁺ : 465; Obtained: 464.9.

Step 2: The above amide (0.04 g, 0.086 mmol) was dissolved in dry DCM (2.0 mL). 0.03 mL, 0.21 mmol DAST was added and the reaction mixture was stirred at a temperature of 0 ° C. for 2 hours. LCMS showed m / z 446.9 of product formation. 0.06 g of solid K ₂ CO ₃ was added at 0 ° C. and the reaction mixture was gradually warmed to room temperature. The reaction mixture _{was diluted with 3} aqueous NaHCO and extracted with DCM (15.0 mL x 3). The organic layer was washed with brine, separated and dried over anhydrous Na ₂ SO ₄ . The crude product was obtained by evaporation of the solvent. Purification was performed by prep TLC (mobile phase: 95:05 DCM: MeOH). 25.0 mg of solid product was obtained. m / z calculated for C ₂₃ H ₁₉ ClN ₆ O ₂ [M + H] ⁺ : 447; Obtained: 446.9.
Synthesis of compound 264:

Step 1: Intermediate B (0.03 g, 0.09 mmol), 0.034 g, 0.17 mmol EDC. HCl and 0.027 g, 0.17 mmol HOBt. xH ₂ O was dissolved in anhydrous DCM (2.5 mL). 0.024 g, 0.17 mmol of S- (+)-2-phenylglycinol was added and the reaction mixture was stirred at room temperature for 6 hours. LCMS showed m / z 464.9 of product formation. The reaction mixture was diluted with deionized water and extracted with DCM (10.0 mL x 3). The combined DCM layers were washed with brine, separated and dried over anhydrous Na ₂ SO ₄ . The crude product was obtained by evaporation of the organic layer. A liquid syrup was obtained. m / z calculated for C ₂₃ H ₂₁ ClN ₆ O ₃ [M + H] ⁺ : 465; Obtained: 464.9.

Step 2: The above amide (0.04 g, 0.086 mmol) was dissolved in dry DCM (2.0 mL). 0.03 mL, 0.21 mmol DAST was added and the reaction mixture was stirred at a temperature of 0 ° C. for 2 hours. LCMS showed m / z 446.9 of product formation. 0.06 g of solid K ₂ CO ₃ was added at 0 ° C. and the reaction mixture was gradually warmed to room temperature. The reaction mixture _{was diluted with 3} aqueous NaHCO and extracted with DCM (15.0 mL x 3). The organic layer was washed with brine, separated and dried over anhydrous Na ₂ SO ₄ . The crude product was obtained by evaporation of the solvent. Purification was performed by prep TLC (mobile phase: 95:05 DCM: MeOH). 26.4 mg of solid product was obtained. m / z calculated for C ₂₃ H ₁₉ ClN ₆ O ₂ [M + H] ⁺ : 447; Obtained: 446.9.

Compounds 180, 181 and 182 were prepared using a synthetic procedure similar to that used for the synthesis of compound 168, as illustrated in Scheme 27.

Compounds 183 to 193 were prepared using a synthetic procedure similar to that used for the synthesis of compounds 169 to 179, as illustrated in Scheme 26.

Compounds 194 and 195 were prepared using synthetic procedures similar to those shown in Schemes 21 and 22.

Compounds 196-198, and 206 were prepared using a synthetic procedure similar to the synthetic procedure illustrated in Scheme 18a.

Compound 202 was prepared using a synthetic procedure similar to that used for the synthesis of compound 129, as illustrated in Scheme 18a.

Compounds 199, 200, 204, and 205 were prepared using a synthetic procedure similar to that illustrated in Scheme 18b.

Compounds 201 and 203 were prepared using a synthetic procedure similar to that shown in Scheme 24.

Compounds 207-210 were prepared using a synthetic procedure similar to that shown in Scheme 17.

Nitrile substituents in compounds 207-210 were produced in a manner similar to the conversion shown in Scheme 22.

Compounds 211-214 were prepared using a synthetic procedure similar to the synthetic procedure illustrated in Scheme 20.

Compound 255 was prepared from suitable starting materials as well as compound 254 using the synthetic routes described in Schemes 28 and 29.

Compound 259 was prepared from the appropriate starting material in a similar manner to compound 243 using the synthetic routes described in Schemes 28 and 29.

Compound 260 was prepared from the appropriate starting material in a similar manner to compound 242 using the synthetic routes described in Schemes 28 and 30.

Compound 261 was prepared from the appropriate starting material in a similar manner to compound 256 using the synthetic routes described in Schemes 28 and 30.

Compound 265 was prepared from the appropriate starting material in a similar manner to compound 264 using the synthetic routes described in Schemes 28 and 30.

Compound 266 was prepared from the appropriate starting material in a similar manner to compound 264 using the synthetic routes described in Schemes 28 and 30.

Compound 267 was prepared from the appropriate starting material in a similar manner to compound 264 using the synthetic routes described in Schemes 28 and 30.

Compound 268 was prepared from the appropriate starting material in a similar manner to compound 263 using the synthetic routes described in Schemes 28 and 30.

Compound 270 was prepared from suitable starting materials as well as compound 264 using the synthetic routes described in Schemes 28 and 30.

Compound 271 was prepared from suitable starting materials as well as compound 264 using the synthetic routes described in Schemes 28 and 30.

Compound 275 was prepared from suitable starting materials as well as compound 264 using the synthetic routes described in Schemes 28 and 30.

Compound 276 was prepared from the appropriate starting material in a similar manner to compound 245 using the synthetic routes described in Schemes 28 and 30.

Compound 278 was prepared from suitable starting materials as well as compound 233 using the synthetic routes described in Schemes 28 and 29.

Compound 281 was prepared from the appropriate starting material in a similar manner to compound 233 using the synthetic routes described in Schemes 28 and 29.

Compounds 282, 283, 286, and 287 were prepared from suitable starting materials in a similar manner to compound 243 using the synthetic routes described in Schemes 28 and 29.

Compound 288 was prepared from suitable starting materials as well as compound 256 using the synthetic routes described in Schemes 28 and 29.

Compound 293 was prepared from the appropriate starting material in a similar manner to compound 285 using the synthetic routes described in Schemes 28 and 29.

Compounds 294, 295, and 296 were prepared from suitable starting materials in the same manner as compounds 243 and 244 using the synthetic routes described in Schemes 28 and 29.

Compound 303 was prepared from suitable starting materials as well as compound 233 using the synthetic routes described in Schemes 28 and 29.

Compound 304 was prepared from suitable starting materials as well as compound 264 using the synthetic routes described in Schemes 28 and 29.

Compound 297 was prepared from the appropriate starting material in a similar manner to compound 243 using the synthetic routes described in Schemes 28 and 29.

Compound 307 was prepared from the appropriate starting material in a similar manner to compound 285 using the synthetic routes described in Schemes 28 and 29.

Compound 308 was prepared from the appropriate starting material using the synthetic pathway described in Scheme 28, as well as Intermediate A.

Compound 309 was prepared from the appropriate starting material in a similar manner to compound 238 using the synthetic routes described in Schemes 28 and 29.

Compound 310 was prepared from suitable starting materials as well as compound 285 using the synthetic routes described in Schemes 28 and 29.

Compound 311 was prepared from the appropriate starting material in a similar manner to compound 285 using the synthetic routes described in Schemes 28 and 29.

Compound 312 was prepared from the appropriate starting material in a similar manner to compound 244 using the synthetic routes described in Schemes 28 and 29.

Compound 313 was prepared from the appropriate starting material in a similar manner to compound 244 using the synthetic routes described in Schemes 28 and 29.
Synthesis scheme 31 of compounds 305 and 306

Compound 288 (0.015 g, 0.042 mmol) was dissolved in anhydrous THF (3.0 mL). After adding 0.003 mL, 0.05 mmol of methyl iodide at a temperature of −78 ° C., 0.05 mL, 0.05 mmol of 1.0 M LDA solution was added. The reaction mixture was stirred at −78 ° C. and gradually warmed to room temperature. LCMS shows a large amount of product formation m / z 368, an unreacted starting material m / z 354, and a dimethylated unknown product m / z 382.1. The reaction mixture _{was quenched with saturated NH 4} Cl solution and extracted with EtOAC. The organic layer was dried and concentrated. Purification of the crude reaction mixture was performed on a prep-TLC plate (mobile phase: EtOAc: hexane 75: 25 v / v mL) to isolate three bands. By MS, the first band confirms the starting material m / z 354, the second band confirms the m / z 368 of compound 305, which is the monomethyl substitution product, and the third band confirms the dimethyl substitution product. It was found that m / z 382.1 of compound 306, which is a substance, was confirmed. ^{1 1} H NMR (CDCl ₃ ) data confirmed the monomethyl substitution on the imidazole ring. NOTE: ^{1 1} H NMR data confirmed product formation and pure product isolation.

Compound 216 was prepared in the same manner as compound 129 in Scheme 18a. MS: [M + 1] = 395.

化合物２１８の合成：

Compound 217 was prepared in the same manner as compound 129 in Scheme 18a. MS: [M + 1] = 381.
Scheme 32

Synthesis of compound 218:

5- (ethoxycarbonyl) -16-methoxy-2,3,4,10,12-pentaazatetracyclo [11.4.0.0] from Scheme 27, stirred at 0 ° C. in DMF (10 ml). ^2,6 . 0 ^8,12] heptadeca-1 (17), 3,5,8,10,13,15- heptaene-9-carboxylic acid (0.609 g, 1.65 mmol) _in, NaHCO 3 (0.749 g, 8. 9 mmol) and NBS (0.793 g, 4.45 mmol) were added. This reaction proceeded overnight at ambient temperature. The reaction was then diluted with EtOAc, cooled to 0 ° C., and saturated sodium thioate was added carefully with stirring. After the foaming stopped, the organic layer was separated _{, washed with saturated NaHCO 3} and brine, and dried with _{silyl 4.} Crude bromide was obtained by filtration and removal of solvent, which was purified by flash column chromatography using gradient elution of 0-80% EtOAc in hexanes. 424.2 mg (64%) was obtained as a yellowish solid. MS: [M + 1] = 405.

CuI (121.5 mg, 0.638 mmol), trimethylsilylacetylene (1.04 g, 10.7 mmol) and triethylamine (0.717 g) were added to the bromide (286.7 mg, 0.709 mmol) from the above in a thick-walled round-bottom flask. , 7.09 mmol), dicyclohexyl (2', 6'-dimethoxybiphenyl-2-yl) phosphine (0.349 g, 0.851 mmol) and 1,4-dioxane (2.5 ml; degassed) were added. The reaction vessel was flushed with nitrogen gas and bis (triphenylphosphine) palladium (II) dichloride (298.2 mg, 0.425 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, then heated at 100 ° C. for 16 hours under sealed tube conditions, diluted with EtOAc _{, washed with saturated NaHCO 3} , brine and dried (regsvr ₄ ). Silica gel column chromatography using a gradient of 100% EtOAc in hexanes from the filtered and concentrated reaction mixture gave 157.9 mg (53%) of the desired trimethylsilylacetylene product as a brownish solid. .. MS: [M + 1] = 422.

The trimethylsilyl alkyne (128.7 mg, 0.305 mmol) obtained above was mixed with lithium hydroxide (36.6 mg, 1.53 mmol) in THF (0.9 ml), water (0.75 ml) and MeOH (0. It was treated at room temperature for 2 hours in a solvent mixture with 15 ml). The mixture was then acidified to pH 3-4 with dilute hydrochloric acid and extracted with EtOAc (3 times). The precipitate remaining in the aqueous layer was found to be a product, so 95.6 mg of acid was obtained as a yellowish solid, collected by filtration and combined with the product isolated from the organic layer. ..

To this acid (95.6 mg, 0.298 mmol) in THF (1.3 ml) and dichloromethane (1.3 ml), N, O-dimethylhydroxylamine hydrochloride (232.4 mg, 2.38 mmol), EDC hydrochloride (456.7 mg, 2.38 mmol), HOBt hydrate (91.2 mg), and triethylamine (0.833 ml, 5.93 mmol) were added. After 16 hours of stirring, the reaction was diluted with EtOAc and washed with _{saturated NH 4 Cl.} The aqueous layer was separated and extracted with EtOAc (3 times), and the combined organic layers were washed with saturated NaHCO ₃ , brine and dried (ethyl ₄ ). After filtration, the solvent was removed to give 104.8 mg of amide as a yellowish solid.

A 4-fluorophenylmagnesium bromide solution (1 M THF; 0.828 ml) to Weinreb amide (20.1 mg, 0.0552 mmol) from above, stirred in anhydrous THF (0.8 ml) cooled in an ice bath. ) Was added slowly. The reaction mixture was stirred at ambient temperature for 4 hours, then _{quenched with saturated NH 4} Cl, extracted with EtOAc (3 times), washed with saturated NaHCO ₃ and brine, and dried (0054 ₄ ). Prep. Using 5% MeOH in DCM of filtered and concentrated mixture. TLC gave 2.0 mg of compound 218 as an off-white solid. MS: [M + 1] = 400.

Compound 219 was prepared in the same manner as compound 218 as illustrated in Scheme 32. MS: [M + 1] = 416.
Synthesis of compound 220:

化合物２２２の合成：

5-Benzoyl-9-ethynyl-16-methoxy-2,3,4,10,12-pentaazatetracyclo [11.4.0.0 ^2,6 . 0 ^8,12] heptadeca-1 (17), 3,5,8,10,13,15- heptaene (90.3mg, 0.237mmol; yield in the same manner as 218) in THF (1.5 ml) of Stirred at room temperature. NaBH ₄ (26.8 mg, 0.71 mmol) was added. After 1 hour, the reaction was _{quenched with NH 4} Cl for 5 minutes and extracted with EtOAC. The organic layer was separated, washed with brine and dried with ו ₄ . Filtration and removal of the solvent under reduced pressure gives a clear viscous oil, which is in DCM (1.5 ml) with triethylsilane (241.9 mg, 2.08 mmol) and trifluoroacetic acid (0.32 ml). Processed for 3 hours. The reaction mixture was placed in Rotobap for solvent removal, diluted with EtOAc and washed with _{saturated NaHCO 3.} The aqueous layer was separated and extracted with EtOAc, and the combined organic layers were washed with brine, and dried over MgSO _4. Prep. Using 2% MeOH in DCM / EtOAc (1: 1) of the filtered concentrate. TLC gave 2.5 mg of compound 220 as a clear film-like solid. MS: [M + 1] = 370.
Compound 221 was prepared in the same manner as compound 220 as illustrated in Scheme 32. MS: [M + 1] = 384.
Scheme 33

Synthesis of compound 222:

Cyanester (407.1 mg, 1.16 mmol) in lithium hydroxide (83.5 mg, 3.49 mmol) in a solvent mixture of THF (6 ml), water (5 ml) and MeOH (1 ml) at room temperature. It was treated for 16 hours, then concentrated under reduced pressure, acidified to pH 3-4 with dilute HCl and cooled at 0 ° C. The precipitate was collected by filtration, washed with a small amount of water and dried to give 271.9 mg (73%) acid as a greyish solid. The acid (271.9 mg) was suspended in THF (2 ml) and stirred at 0 ° C. to which borane dimethyl sulfide solution (2 M THF; 8.4 ml) was added dropwise. The reaction was allowed to proceed overnight at ambient temperature, cooled in an ice bath, quenched with MeOH (10 ml) for 2 hours, and concentrated under reduced pressure. The resulting solid residue was _{partitioned between DCM and saturated NaHCO 3} and stirred for 20 minutes. The aqueous layer was separated and extracted with DCM (3 times). The combined organic layers were washed with brine and dried with י ₄ . Filtration and removal of solvent gave 137.8 mg of crude alcohol product as a yellowish waxy solid.
The alcohol (137.8 mg) from the above was treated with phosphorus oxybromide (256.3 mg, 0.894 mmol) in 1,4-dioxane (5 ml) at 100 ° C. for 3 hours. After cooling in an ice bath, the reaction mixture was _{treated with saturated NaHCO 3} (15 ml) and EtOAc (15 ml) under stirring conditions for about 20 minutes. The basic aqueous layer was separated and extracted with EtOAc (twice). The combined organic layers were washed with brine and dried with י ₄ . By filtration and removal of the solvent under reduced pressure, a crude primary bromide was obtained as a solid paste, which was stored in a cold place and used when needed without further purification.
The crude bromide from the above (27.0 mg, 0.0727 mmol) was treated with 4-fluorophenol (65.2 mg, 0.585 mmol) and cesium carbonate (47.4 mg, 0.145 mmol) at room temperature for 16 hours. The reaction mixture was diluted with EtOAc, washed with brine, and dried over MgSO _4. Prep. Using 5% MeOH in DCM / EtOAc (1: 1) of the filtered concentrate. TLC gave 1.2 mg of compound 222 as a yellowish solid. MS: [M + 1] = 403.

Compound 223 was prepared in the same manner as compound 222 as illustrated in Scheme 33. MS: [M + 1] = 403.

Compound 224 was prepared in the same manner as compound 222 as illustrated in Scheme 33. MS: [M + 1] = 385.

Compound 225 was prepared in the same manner as compound 222 as illustrated in Scheme 33. MS: [M + 1] = 464.
Scheme 34

Ethyl 1- (5-chloro-2-nitrophenyl) -5- (2-ethoxy-2-oxoethyl) -1H-1,2,3-triazole-4-carboxylate (21.2 g; with 14 of Scheme 11) Similarly obtained) was treated with tin (II) chloride hydrate (60 g) in a solvent mixture of EtOAc / EtOH (1: 2,300 ml) at 70 ° C. for 3 hours. HCl (40 ml; 37%) was added and heating continued for 3 days. Further tin (II) chloride hydrate (25 g) and HCl (15 ml) were added and heating was continued for 2 days. The reaction was cooled and concentrated under reduced pressure to give a brownish oil, diluted with EtOAc (250 ml) and carefully basified to pH 8-9 using sodium carbonate solution. The aqueous layer was separated and repeatedly extracted with EtOAc. The combined organic layers were washed with brine and dried with י ₄ . Filtration and removal of solvent followed by recrystallization in MeOH gave 3.3 g (51%) of the cyclized monoester as a yellowish solid. MS: [M + 1] = 307.
Preparation of tert-Butyl Isocyanoacetate:

In a suspension of glycine tert-butyl hydrochloride (10.0 g, 60 mmol) in DCM (200 ml), EDC. HCl (14.9 g, 78 mmol) and triethylamine (12.5 mL, 89.8 mmol) were added. The reaction mixture was cooled to −50 ° C. and formic acid (3.4 mL, 89.8 mmol) in DCM (10 mL) was added slowly. The reaction mixture was stirred at −50 ° C. for 1 hour and then at 4 ° C. for 3 hours. Water (150 ml) was added. After stirring for 30 minutes, the aqueous layer was separated and extracted with DCM (3 times). The combined organic layers were washed with brine and dried with י ₄ . Filtration and removal of the solvent under reduced pressure gave 10 g (100%) of formylamide as a clear viscous oil. H ¹ NMR (CDCl ₃ ) δ 8.23 (1H, s), 6.17 (1H, br s), 3.98 (2H, d, J = 5.5Hz), and 1.48 (9H, s).

Triethylamine (36.8 mL, 264 mmol) was added to a solution of formylamide (10.5 g, 66 mmol) in DCM (180 mL). The solution was cooled in a salt-ice bath and POCl ₃ (7.4 mL, 79.2 mmol) was added slowly. The reaction was stirred in this cold bath for 1 hour. Sodium carbonate (7.7 g, 72.6 mmol) in water (90 ml) was then added to the cold reaction mixture. After 15 minutes, the cold bath was removed and stirring was continued for 1 hour at ambient temperature. The aqueous layer was separated and extracted with DCM (3 times). The combined organic layers were washed with brine and dried with י ₄ . Filtration and removal of the solvent under reduced pressure gave 7.9 g (84%) of tert-butyl isocyanoacrylate as a dark brown liquid. H ¹ NMR (CDCl ₃ ) δ 4.12 (2H, s), and 1.51 (9H, s).

A solution of tert-butyl isocyanoacetate (1.51 g, 10.7 mmol) in DMF (43 ml) was cooled to −50 ° C. under a nitrogen atmosphere. Potassium t-butoxide (1.05 g, 9.4 mmol; crushed thinly) was added. After stirring at −50 ° C. for 1 hour, 1,2,4-triazole intermediate (2.32 g, 6.48 mmol; prepared similarly to compound 20 of Scheme 11) was added to this resulting reddish clear solution. It was added and the reaction was stirred at ambient temperature overnight. Saturated NaHCO ₃ (15 ml) was added and the reaction mixture was extracted with diethyl ether (5 times), washed with brine and dried (ו ₄ ). Silica gel chromatography using a gradient of 0-100% EtOAc in hexanes from the filtered concentrate gave 2.5 g (89%) of the imidazole t-butyl ester product as a yellowish solid. MS: [M + 1-tBu] = 374.

The imidazole t-butyl ester (1.1 g, 2.56 mmol) from the above with trifluoroacetic acid (13 ml) in DCM (13 ml) for 3 hours or until all starting t-butyl esters are hydrolyzed. , Processed. The reaction was then concentrated under reduced pressure. Residual TFA was removed by repeated addition of toluene and evaporation. The acid product was obtained as a dark brown viscous oil, which was used without further purification. MS: [M + 1] = 374.

Ethyl 16-chloro-9-cyano-2, 3, 4, 10, 12-pentaazatetracyclo [11.4.0.0 ^2,6 . 0 ^8,12] heptadeca-1 (17), 3,5,8,10,13,15- heptaene-5-carboxylate (477 mg, 1.34 mmol); ethyl Scheme 27 9-cyano-16-methoxy - 2,3,4,10,12-pentaazatetracyclo [11.4.0.0 ^2,6 . 0 ^8,12] heptadeca-1 (17), the 3,5,8,10,13,15- heptaene -5-like the carboxylate), lithium hydroxide (80.5 mg, 3.36 mmol) Then, the treatment was carried out at room temperature for 16 hours in a solvent mixture of THF (6 ml), water (5 ml) and MeOH (1 ml). The reaction was concentrated under reduced pressure, acidified to pH 3-4 with dilute HCl and cooled to 0 ° C. The precipitate was collected by filtration, washed with a small amount of water and further dried to give 396.2 mg of crude triazolocarboxylic acid product. MS: [M + 1] = 327.

A borane dimethyl sulfide complex (10.9 ml; 2M THF) was added dropwise at 0 ° C. to a suspension of the crude acid (396.2 mg) from above in anhydrous THF (7 ml). The reaction was allowed to proceed overnight at ambient temperature, then cooled to 0 ° C. and then slowly quenched with MeOH. After stirring for 30 minutes, the reaction mixture was concentrated under reduced pressure. The resulting slurry was treated with MeOH and then removed under reduced pressure. This process was repeated several times. The resulting residue was then treated with 5% MeOH in DCM and washed with _{saturated NaHCO 3.} The aqueous layer was extracted with DCM (3 times), the combined organic layers were washed with brine and dried with ו ₄ . Filtration and removal of the solvent gave a mixture of the crude alcohol product ([M + 1] = 313) and the corresponding primary amide ([M + 1] = 331) due to the hydrolysis of the cyano group. 388.8 mg of this composition mixture was obtained and used without further purification.

The alcohol mixture (388.8 mg) from the above was treated with phosphorus oxybromide (2.02 g) in 1,4-dioxane (10 ml) at 100 ° C. for 8 hours. The reaction was cooled to 0 ° C. _{and carefully quenched with saturated NaHCO 3} (15 ml). After stirring for 20 minutes, the reaction mixture was extracted with EtOAc (3 times), washed with brine and dried with י ₄ . Filtration and removal of the solvent under reduced pressure gave the crude bromide as a viscous paste, which was used in the next step without further purification.

Compound 226 was prepared using the bromide prepared above, as was compound 222 in Scheme 33. MS: [M + 1] = 389.

Compound 227 was prepared in a manner similar to compound 226 illustrated in Scheme 34. MS: [M + 1] = 407.

化合物２２９の合成： Compound 228 was prepared in a manner similar to compound 226 illustrated in Scheme 34. MS: [M + 1] = 407.
Scheme 35

Synthesis of compound 229:

The benzyl analog 229 shown in Scheme 35 was prepared in the same manner as the benzyl compound 220 in Scheme 32. MS: [M + 1] = 411.
Synthesis of compound 230:

The ketone analog 230 shown in Scheme 35 was prepared in the same manner as the ketone 218 in Scheme 32. MS: [M + 1] = 474.
Synthesis of compound 231:

The benzyl analog 231 shown in Scheme 35 was prepared in the same manner as the benzyl compound 220 in Scheme 32. MS: [M + 1] = 460.
Scheme 36

Compound 63 (0.805 g, 1.78 mmol; from scheme 18a) in lithium hydroxide (0.128 g, 5.34 mmol) in a solvent mixture of THF (6 ml), water (5 ml) and MeOH (1 ml). Was treated at room temperature for 16 hours. The reaction was then concentrated under reduced pressure and acidified to pH 3-4 with dilute HCl. The resulting precipitate was collected by filtration, washed with water and dried to give 0.638 g of acid as a yellow solid. MS: [M + 1] = 424.
The acid from the above (0.638 g, 1.5 _{mmol) was treated with NBS (1.61 g, 9 mmol) and NaHCO 3} (1.51 g, 18 mmol) at room temperature for 16 hours. The reaction mixture was cooled to 0 ° C. and saturated sodium thionate (aqueous solution) was added carefully and slowly. It was extracted with EtOAc (twice), washed with saturated NaHCO ₃ and brine, and dried with _{silyl 4.} Silica gel chromatography on the filtered concentrate with a gradient of 0-100% EtOAc in hexanes gave 0.580 g (72%) of the di-bromo product as a yellowish solid. MS: [M + 1] = 538.

Compound 232 was prepared using the bromide prepared above, as was compound 55 in Scheme 18a. MS: [M + 1] = 439.

Compound 235 was prepared using the bromide prepared above, as was compound 55 in Scheme 18a. MS: [M + 1] = 440.

Compound 236 alkyne moieties were prepared in the same manner as in Scheme 21 compound 161. MS: [M + 1] = 384.

化合物２４７の合成： The compound 241 alkyne moiety was prepared in the same manner as compound 161 of Scheme 21. MS: [M + 1] = 385.

Synthesis of compound 247:

Bromide ester (13.9 mg, 0.0344 mmol) in lithium hydroxide (10 mg) in a solvent mixture of THF (0.3 ml), water (0.25 ml) and MeOH (0.05 ml) at room temperature. Processed for 16 hours. The reaction was then concentrated under reduced pressure, acidified to pH 3-4 with dilute HCl and cooled to 0 ° C. The resulting precipitate was collected by filtration, washed with water and dried to give 9.5 mg (74%) of acid as a light brown solid. MS: [M + 1] = 377.
Oxalyl chloride (8.6 mg, 0.0678 mmol) and DMF (5 ul) were added to the acid (5.1 mg, 0.0136 mmol) from above, stirred in DCM (0.15 ml). After stirring for 2 hours, the solvent and excess reagent were removed under reduced pressure. The resulting residue was resuspended in DCM (0.15 ml), cooled in an ice-salt bath, and ethanolic methylamine (100 ul; 33%) was added dropwise. After stirring for 20 minutes, the reaction mixture was prep. It was applied to a TLC plate and isolated using 5% MeOH in DCM as an eluent. 4.3 mg (81%) of compound 247 was obtained as a white solid. MS: [M + 1] = 390.

Compound 248 was prepared as shown in Scheme 32, similar to compound 247. MS: [M + 1] = 430.

Oxalyl chloride (170.1 mg, 1.34 mmol) was slowly added to the above acid (108.0 mg, 0.335 mmol) suspended in DCM (2 ml) at 0 ° C., and then DMF (20 ul) was added. .. After the gas generation stopped, the ice bath was removed and the reaction proceeded at room temperature for 2 hours. The solvent and excess reagent were removed under reduced pressure. The resulting light brown solid was cooled to 0 ° C. A _{solution of NaBH 4} (2.2 ml; 1.5 M in methoxyethoxyethane) was added. After 30 minutes, the reaction was quenched with 1N HCl (0.2 ml) and stirring was continued until the formation of bubbles stopped. EtOAc (10 ml) and saturated NaHCO ₃ (10 ml) were added and this was stirred overnight. The aqueous layer was separated and extracted with EtOAc (3 times); the combined organic layers were washed with brine and dried with ו ₄ . Filtration and removal of solvent gave 97.0 mg (94%) of alcohol as a yellowish solid. MS: [M + 1] = 309.

The alcohol from the above (97.0 mg, 0.315 mmol) was treated with Dess-Martin peryodinane (266.9 mg, 0.629 mmol) in DCM (2 ml) for 1 hour. The reaction mixture was diluted with DCM and washed with _{saturated NaHCO 3.} The aqueous layer was separated and extracted with DCM (3 times), the combined organic layers were washed with brine and dried with ו ₄ . Filtration and removal of the solvent under reduced pressure gave a quantitative yield of crude aldehyde as a brownish solid, which was used without further purification.

Compound 250 was prepared as illustrated in Scheme 33 using the aldehydes from above, similar to Compound 48 in Scheme 16. MS: [M + 1] = 362.

Compound 251 was prepared as illustrated in Scheme 33, similar to compound 250. MS: [M + 1] = 376.

Compound 252, like compound 250, was prepared as illustrated in Scheme 33. MS: [M + 1] = 364.

Compound 253, like compound 250, was prepared as illustrated in Scheme 33. MS: [M + 1] = 452.
Scheme 37

The acid (16 of Scheme 15, X = OME; 258.1 mg, 0.941 mmol) was treated with acetic acid (2 ml) at 120 ° C. for 5 hours. The solvent was then removed under reduced pressure. The solid residue was treated with water (7 ml) while sonicating, filtered, washed with water and dried to give 158.4 mg (73%) of the decarboxylation product as a brownish solid. MS: [M + 1] = 231.

Compound 257 was prepared in a manner similar to Compound 167 in Scheme 11. MS: [M + 1] = 364.

Compound 258 was prepared in a manner similar to Compound 167 in Scheme 11. MS: [M + 1] = 336.
Synthesis of compound 262:

Benzyltriphenylphosphonium bromide (29.0 mg, 0.0669 mmol) was stirred in THF (0.5 ml) cooled in a salt-bath. Sodium hydride (4.12 mg, 0.103 mmol; 60% oil suspension) was added. After stirring for 20 minutes, aldehyde (15.8 mg, 0.0515 mmol) was added. The reaction was slowly warmed to room temperature over 4 hours, then _{quenched with saturated NH 4} Cl, extracted with EtOAc (3 times), washed with brine and dried with regsvr ₄ . Compound 262 was repeatedly prep. Using 2% MeOH in DCM. Isolated by TLC. 1.1 mg was isolated as a white solid. MS: [M + 1] = 381.

The starting ester (76.4 mg, 0.235 mmol) was treated with N-bromosuccinamide (83.6 mg, 0.470 mmol) in acetonitrile (2.3 ml) at room temperature for 3 days. Saturated sodium thioate was added to this reaction mixture. After stirring for 15 minutes, the aqueous layer was separated and extracted with EtOAc (twice). The combined organic layers were washed with brine and dried with י ₄ . The bromide product is prepared using hexane: EtOAc = 1: 3 as the elution solvent. Isolated by TLC. 50.2 mg (52%) was obtained as a light brown foamy solid. MS: [M + 1] = 405.

The bromide (24.1 mg, 0.0596 mmol) from the above, phenylboronic acid (10.3 mg, 0.083 mmol), tetrakis (triphenylphosphine) palladium (0) (6.9 mg, 0.) under a nitrogen atmosphere. 006 mmol), dimethoxyethane (0.69 mL; degassed), and an _{aqueous Na 2} CO ₃ solution (77 ul; 2 M) were added. The reaction was heated for 5 hours at 100 ° C., cooled to room temperature, diluted with EtOAc, washed with saturated NaHCO _3, brine, and dried over MgSO _4. Hexane: EtOAc = 1: 3 Prep. TLC gave 17.2 mg (72%) Suzuki coupling product as a yellowish amorphous material. MS: [M + 1] = 402.
Synthesis of compounds 272, 273 and 277:

Compound 272 was prepared starting from the imidazole ester described above, similar to compound 167 in Scheme 11. MS: [M + 1] = 440.

Compound 273 was prepared starting from the imidazole ester described above, similar to compound 167 in Scheme 11. MS: [M + 1] = 412.

Compound 277 was prepared in the same manner as compound 167 in Scheme 11. MS: [M + 1] = 378.

化合物２８０の合成： Compound 279 was prepared by Suzuki coupling in a manner similar to that detailed above (see Scheme 37). MS: [M + 1] = 436.

Synthesis of compound 280:

Compound 267 (11.7 mg, 0.0274 mmol), dicyclohexyl [2- (2,4,6-triisopropylphenyl) phenyl] phosphine (7.8 mg, 0.0164 mmol), cesium carbonate (22) under a nitrogen atmosphere. .3 mg, 0.0685 mmol), and acetonitrile (0.30 ml) were added. The reaction flask was flushed with nitrogen gas and dichlorobis (acetonitrile) palladium (II) (1.42 mg, 0.0055 mol) was added. After stirring at room temperature for 30 minutes, trimethylsilylacetylene (80.7 mg, 0.822 mmol) is added and the reaction is heated at 90 ° C. for 5 hours, cooled to room temperature, diluted with EtOAc and saturated NaHCO ₃ Washed with. The aqueous layer was separated and extracted with EtOAc (twice), the combined organic layers were washed with brine and dried with י ₄ . Prep. Using 5% MeOH in DCM / EtOAc (1: 1) of the filtered concentrate. TLC gave 4.1 mg of trimethylsilylacetylene derivative as a yellowish solid. MS: [M + 1] = 489.

Trimethylsilylacetylene (4.1 mg, 0.0084 mmol) from the above was treated with potassium carbonate (1.2 mg, 0.0084 mmol) in methanol (0.2 ml) at room temperature for 3 hours. Prep. Using 7% MeOH in DCM / EtOAc (1: 1) as the elution solvent. TLC gave 1.6 mg of compound 280 as a yellowish solid. MS: [M + 1] = 417.
Synthesis of compounds 284, 301 and 302:

Compound 284 was prepared starting from compound 240, as was compound 280. MS: [M + 1] = 403.

Compound 301 was prepared starting from compound 264, as was compound 280. MS: [M + 1] = 437.

化合物２８９、２９０、２９１および２９２の合成： Compound 302 was prepared starting from compound 245, as was compound 280. MS: [M + 1] = 435.

Synthesis of compounds 289, 290, 291 and 292:

Compound 289 was prepared as illustrated in Scheme 30, similar to compound 263. MS: [M + 1] = 399.

Compound 290 was prepared as illustrated in Scheme 30, similar to compound 263. MS: [M + 1] = 399.

Compound 291 was prepared as illustrated in Scheme 29, similar to compound 243. MS: [M + 1] = 337.

化合物２９８の合成： Compound 292 was prepared as illustrated in Scheme 29, similar to compound 243. MS: [M + 1] = 337.

Synthesis of compound 298:

The ester (107.9 mg, 0.264 mmol) in THF (2.4 ml) was treated with a lithium borohydride solution (0.264 ml; 2 M THF) at 0 ° C. Allowed to warm to ambient temperature over a reaction for 4 hours, then slowly quenched with saturated NaHCO _3, extracted with EtOAc (4 times), washed with brine, and dried over MgSO _4. Filtration and removal of solvent gave 77.3 mg (86%) alcohol as a yellowish solid.

The alcohol from the above (16.4 mg, 0.0448 mmol) was treated with phosphorus oxybromated (25.7 mg, 0.0895 mmol) in 1,4-dioxane (0.5 ml) at 95 ° C. for 3 hours. The reaction was then cooled to 0 ° C., and quenched 20 minutes with saturated NaHCO ₃ (5 ml), and extracted with EtOAc (3 times), washed with brine, and dried over MgSO _4. Filtration and drying gave 16.6 mg of a yellowish solid, which was dissolved in anhydrous MeOH (18 ul) and THF (0.35 ml). It was cooled to 0 ° C. and NaH (9.2 mg; 60% suspension) was added. After stirring for 2 hours at 0 ° C., the reaction was quenched with saturated NaHCO _3, extracted with EtOAc (3 times), washed with brine, and dried over MgSO _4. Prep. Using 10% MeOH in DCM. TLC gave 0.8 mg of compound 298 as a yellowish solid. MS: [M + 1] = 381.

化合物２９９および３００の合成 The starting alcohol (616 mg) was converted to the corresponding bromide as described above (see Scheme 21). The resulting crude bromide was dissolved in anhydrous methanol (23 ml) and cooled to 0 ° C. NaH (932 mg; 60% suspension) was added in small portions. After the gas generation stopped, the reaction mixture was heated to reflux for 30 minutes, then cooled to room temperature and treated with 2N HCl (11 ml). The resulting precipitate was collected by filtration and the desired methyl ether was isolated by silica gel chromatography using gradient elution of 0-10% MeOH in DCM. 217 mg was collected as a yellowish solid. MS: [M + 1] = 279.

Synthesis of compounds 299 and 300

Compound 299 was prepared using the above-mentioned methyl ether intermediate in the same manner as in Compound 289. MS: [M + 1] = 461.

Compound 300 was prepared using the above-mentioned methyl ether intermediate in the same manner as in Compound 289. MS: [M + 1] = 385.

Compounds 180-313 were characterized by ^{MS and 1 1 H NMR.} This MS characterization is summarized in Table 5 below.

実施例１０５：α５含有ＧＡＢＡ_Ａレセプター（ＧＡＢＡ_ＡＲ）ポジティブアロステリックモジュレーター活性の評価 When performing similar and similar reactions to the reactions shown in Schemes 1-37, the following compounds are also expressly contemplated in this application:

Example 105: .alpha.5 Evaluation of containing GABA _A receptor (GABA _A R) positive allosteric modulator activity

Step 1: GABA _A R-subunit preparation of clones established and corresponding cRNA of (α5, β3, γ2, α1 , α2 and _{α3): GABA A -Rα5, β3} , γ2, α1, α2 and .alpha.3 subunit of human Clone is obtained from a commercial source (eg, OriGene, http: //www.origene.com and Genescript, http: //www.genescrit.com). These clones are engineered to be inserted into pRC, pCDM, pcDNA and pBluescript KSM vectors (for expression in oocytes) or other equivalent expression vectors. Transfect host cells with conventional transfection agents (eg, FuGene, Lipofectamine 2000 or others).

Α5β3γ2 in step 2-Xenopus oocyte expression system, α1β3γ2, α2β3γ2 and α3β3γ2 subtypes functional GABA _A R Assay: α5, β3, γ2, α1 , the cRNA encoding the α2 and α3 subunits, T3 mMESSAGE mMACHINE Transcribed in vitro using Kit (Ambion) and injected from Xenopus laevis into freshly prepared oocytes (in α: β: γ = 2: 2: 1 ratio or other optimized conditions). .. After 2 days of culture, GABAergic Cl-currents from oocytes are measured using TEVC settings (Warner Instruments, Inc., Foster City, CA). GABA, benzodiazepines and diazepam are used as reference compounds to validate this system.

Step 3-Evaluation of the positive allosteric modulator activity of the test compound against the α5β3γ2 subtype, and testing of off-target activity against the β3γ2 subtype to which α1-α3 is bound when the EC50 = 5 μM selectivity cutoff is reached: from oocytes. GABAergic Cl-current is measured in the TEVC setting in the presence of the test compound. The positive allosteric modulator activity of each test compound is tested in a 5-point dose-response assay. The test compounds include several reference compounds (the EC50 values in the literature for the α5β3γ2 subtype are in the range of 3-10 μM). Obtain an EC50 in the α5β3γ2 subtype for each compound. When the EC50 in α5β3γ2 is ≦ 5 μM, the EC50s of the other three subtypes (α1β2γ2, α2β3γ2 and α3β3γ2) are further individually tested to test the selectivity of the compound in the α5β3γ2 subtype over the other subtypes. Measure.

Step 4-Evaluation of additional test compounds for α5β3γ2 subtype, and testing of off-target activity when EC50 = 0.5 μM selectivity cutoff is reached: Second batch of test compounds using the same strategy but with a lower EC50. Test with a cutoff (0.5 μM). Again, the EC50 of the α5β3γ2 subtype for each compound is measured. Only when the EC50 for the α5-containing receptor is <0.5 μM is the β3γ2 subtype bound to α1-α3 tested.
Example 106: _{Evaluation of Compounds for GABA A} α5 Receptor Binding Activity and Positive Allosteric Modulator Activity (A) Binding Activity of Test Compound to _{GABA A R}

Tissue culture and membrane preparation: GABA _A receptors: Ltk cells (provided by Merck Co., NJ, USA) that stably express α1β1γ2, α2β3γ2, α3β3γ2 and α5β3γ2 were bound. Cells were seeded at 5% CO2 in 100 mm culture plates containing DMEM / F12 medium containing 10% serum and antibiotics and grown for 1-2 days. Then, as described below, to induce the expression of GABA _A R by dexamethasone: .alpha.5 case containing GABA _A R is 1 day at 0.5 [mu] M, and [alpha] 1, in the case of α2 and α3-containing GABA _A R, at 2μM 3 days. After induction, cells were harvested by scraping into Dulbeccoline buffered saline (DPBS, pH 7.4, Invitrogen, Carlsbad, CA, USA) and centrifuged at 150 xg for 10 minutes. The pellet was washed twice by resuspension and centrifugation. Cell pelletes from at least 5 different preps are combined, suspended in binding assay buffer (50 mM KH2PO4; 1 mM EDTA; 0.2 M KCl, pH 7.4) and sonicated using Branson Sonifier150 (G. Heinmann, Germany). Membranes were prepared by sonication (3-5 times, 30 seconds). Protein content was measured by BCA assay (Bio-Rad Labs, Reinach, St. Louisland) using bovine serum albumin (Sigma Aldrich, St. Louis, MO, USA) as a reference material. Aliquots were prepared and stored at −20 ° C. for further use in the binding assay.

Ligand binding: the film, ^[3 H] Rol5-1788 of ascending concentrations (0.01~8nM) by incubating (Flumazepil, 75~85Ci / mmol, PerkinElmer , MA, USA) and a saturated bond curve Obtained. Non-specific binding was measured in the presence of 10 μM diazepam. Α1 is determined from the saturation curve, [alpha] 2, the concentration of the radioligand in α3 and α5 containing GABA _{A K d} values for R or below _{K d} values, the ^[3 H] Rol5-1788 inhibition of binding of the test compound gone.

All binding assays were performed at 4 ° C. in assay buffer for 1 hour. All assay volume, .alpha.5-containing GABA _A 0.5ml For R film containing 0.2 mg / ml protein and [alpha] 1, in the case of α2 and α3-containing GABA _A R film was 0.5ml containing 0.4 mg / ml rice field. Incubation was terminated by filtering through a GF / B filter using 24-Cell Harvestor (Brandel, Gaithersburg, MD, USA) and then washing 3 times with ice-cooled assay buffer. The filter was transferred to a scintillation vial, 5 ml of scintillation solution was added, vortexed and mixed, and maintained in the dark. The next day, radioactivity was obtained using a scintillation counter (Beckman Coulter, Brea, CA, USA). All assays were performed in triads.

Data analysis: Saturation and inhibition curves were obtained using GraphPad Prism software (GraphPad Software, Inc., CA, USA). Equilibrium dissociation constant of unlabeled ligand _{(K i} values), Cheng-Prusoff equation _{K i = IC 50 / (1} + S / K d) were determined using (wherein, _{IC 50} ^is the ^[3 H] Ligand The concentration of the unlabeled ligand that inhibits 50% of the binding, S is the concentration of the radioligand, and K _d is the equilibrium dissociation constant of the radioligand). By using the log range of the compound (1 nM to 10 [mu] M), _{K i} values were determined, expressed as the mean ± SD from triplicate assays.
(B) α5β2γ2 subtype GABA _A positive allosteric modulator activity of a test compound on R

First, using essentially similar protocol and presented protocol above, the compounds of the invention were screened in 100nM for the ability to increase the _{EC 20} concentration of GABA in the oocytes containing the GABA _A receptor (α5β2γ2) ..

On day 1, 1 ng / 32 nL GABA _A α5β2γ2 cDNA was injected into one oocyte. The test starts on the second day. The cDNA injected into the oocyte is a mixture of alpha, beta and gamma, the ratio of which is 1: 1:10 (weight basis) and the mixture to be injected in one oocyte. The total weight of the three subunits was 1 ng in a volume of 32 ln. The injected oocytes can also be tested on day 3. In such cases, the amount of cDNA injected into the oocyte should be reduced by 20%.

The compounds of the invention were tested using the following procedure.

GABA Dose Response 1) Eight oocytes were placed in eight chambers of OpusXpress and surface perfused with modified Bath saline (MBS) at 3 mL / min. A glass electrode (0.5-3 megaohms) refilled with 3M KCl was used. The membrane potential of the oocyte was fixed at -60 mV.
2) In order to stabilize the oocytes, the average EC ₂₀ GABA obtained from the previous test was applied 5 to 6 times. During each GABA application, oocytes were washed with MBS for 5-10 minutes.
3) A GABA dose response was performed to obtain an _{EC 20 GABA value.}

Control test (diazepam or methyl 3,5-diphenylpyridazine-4-carboxylate)
1) A new test was performed using new oocytes.
_{2) EC 20} GABA was applied 5 to 6 times to stabilize the oocytes. During each GABA application, oocytes were washed with MBS for 5-10 minutes.
3) _{By applying EC 20} GABA, a current (I _GABA ) was obtained. Oocytes were washed with MBS for 5-10 minutes.
4) Pre-apply 1 μM diazepam or methyl 3,5-diphenylpyridazine-4-carboxylate for 40 seconds, then apply 1 μM diazepam or methyl 3,5-diphenylpyridazine-4-carboxylate _{simultaneously with EC 20} GABA. As a result, I _test was obtained. Augmentation (%) was obtained by dividing I _test by I _GABA.

In the test compound 1) control test a plurality of times, the above steps 1), 2) and 3) are repeated.
2) After pre-applying the first concentration of the test compound for 40 seconds _{, the test} was obtained by simultaneous application of _{the same concentration of the test compound and EC 20 GABA.} The enhancement (%) is obtained by dividing _{I test} by I _GABA.
3) All the tested oocytes were discarded and new oocytes were used to test the same compound at a second concentration by repeating steps 1) and 2) above. Each oocyte was used for only one concentration test for a single test compound. These steps were repeated for the other test compounds.

In some embodiments, compounds of the present application, less than 200 nM, less than 180 nM, binding affinity of α5 containing GABA _A R less than 150nM or less than 100nM (represented by _{K i).} In some embodiments, compounds of the present application, has a binding affinity for α5 containing GABA _A R less than 50 nM (represented by _{K i).} In some embodiments, compounds of the present application has binding affinity for α5 containing GABA _A R less than 10nM (represented by _{K i).}

In some embodiments, compounds of the present application are selective for α5 containing GABA _A R than α1-containing GABA _A R. In some embodiments, compounds of the present application, 50 fold relative to the α1-containing GABA _A R .alpha.5-containing than GABA _A R, 100-fold, 500-fold or 1000-fold super selective.

In some embodiments, the compounds of the present application has a 500nM below, .alpha.5-containing GABA _{A EC 50} of R of less than 100nM or less than 50 nM. In some embodiments, the compounds of the present application has an _{EC 50} of α5 containing GABA _A R of less than 25 nM.

In some embodiments, compounds of the present invention, in 100 nM, .alpha.5-containing GABA _A R more than 10%, greater than 25 percent, ultra enhanced than 50% or 75%. In some embodiments, compounds of the present invention, in 1000 nM, .alpha.5-containing GABA _A R more than 10%, greater than 25 percent, ultra enhanced than 50% or 75%.

The screening results of the binding activity test and the PAM function activity test are summarized in Tables 1 and 2 below.

Table 1 below shows the range of GABAα5 binding Ki associated with the compounds of the invention:

Table 2 below shows the extent of functional enhancement of GABAα5 associated with the compounds of the invention:

The selected compounds of the invention exhibit> 10-fold binding selectivity for GABAα1, GABAα2 or GABAα3.
Example 107: Effect of Methyl 3,5-diphenylpyridazine-4-carboxylate on Elderly Disordered (AI) Rats

van Niel et al., J. van Niel et al. Med. Chem. 48: 6004-6011 methyl 3,5-diphenyl-4-carboxylate corresponding to the compound No. 6 in (2005) is a selective α5 containing GABA _A R agonists. It has an α5 in vitro efficacy of +27 _{(EC 20).} The effect of methyl 3,5-diphenylpyridazine-4-carboxylate on aged rats was investigated using a RAM task. Furthermore, the receptor occupancy by methyl 3,5-diphenylpyridazine-4-carboxylate in the α5-containing GABA _{A receptor was also investigated.}
(A) Effect of methyl 3,5-diphenylpyridazine-4-carboxylate on elderly disabled rats using radial maze (RAM) behavioral tasks

The effect of methyl 3,5-diphenylpyridazine-4-carboxylate on in vivo spatial memory retention in aging disorder (AI) rats, vehicle control and four different dose levels of methyl 3,5-diphenylpyridazine-4-carboxylate. Evaluated in a radial labyrinth (RAM) behavioral task using (0.1 mg / kg, 0.3 mg / kg, 1 mg / kg and 3 mg / kg, ip). RAM behavioral tasks were performed on 8 AI rats. All 5 treatment conditions (vehicle and 4 dose levels) were tested in all 8 rats.

The RAM device used consisted of eight tracks arranged equidistantly. The runway of the elevated maze (width 7 cm x length 75 cm) protruded from each side of the octagonal central platform (diameter 30 cm, height 51.5 cm). The transparent side wall on the track is 10 cm high and is bent at an angle of 65 ° to form a depression. A food well (4 cm in diameter and 2 cm in depth) was located at the distal end of each track. Flot Loops ^TM (Kellogg Company) was used as a reward. A block (height 30 cm x width 12 cm) constructed with ^{Plexiglas TM} could be placed to prevent entry into any track. It also provided a number of additional maze clues around the device.

AI rats were first subjected to a pre-training test (Chappel et al., Neuropharmacology 37: 481-487, 1998). The pre-training test includes a acclimation period (4 days), a training period (18 days) for a standard win-shift task, and a subset of runways (eg, 5 runs) designated by the experimenter. Another training period (14 days) that imposes a short delay time while presenting (that is, three tracks are blocked), as well as an eight-way win-shift task (ie, all eight tracks). Is passable).

During the acclimation phase, the rats were accustomed to the maze during an 8-minute session for 4 consecutive days. In each of these sessions, food rewards were scattered on the RAM, first on the central platform and on the track, and then gradually confined to the track. After this acclimation period, standard training protocols were used. In that protocol, food pellets were placed at the end of each track. Rats were tried once daily for 18 days. Each daily trial was terminated when all 8 food pellets were obtained, or when 16 selections were made or 15 minutes had passed. After this training period was completed, a second training period was conducted. The second training period increased memory requirements by imposing a short delay between trials. At the beginning of each trial, three tracks in the eight-way maze were blocked. Rats were able to obtain five runway foods that were allowed access during this first "information phase" of the trial. Rats were then removed from the maze for 60 seconds, during which time the barriers on the maze were removed to allow access to all eight tracks. Rats were then returned to the central platform and were able to be rewarded for the remaining food during the "memorization test" phase of this trial. Which track was blocked and its placement varied from trial to trial.

The number of "errors" made by AI rats during the memorization inspection period was tracked. If those rats enter a runway where food has already been recovered in the component before the delay time of the trial, or if they revisit the runway already visited in a session after the delay time, the trial is incorrect. Has occurred.

After the pre-training test is completed, the delay time interval between the information period (presentation of some blocked tracks) and the memorization test (presentation of all tracks) is further extended, ie, 2 hours. Rats were subjected to a trial of the delay time. During the delay time interval, the rats were placed on carts in separate home cages by the labyrinth in the laboratory. Thirty to forty minutes prior to daily trials, AI rats were subjected to the following five conditions: 1) vehicle control-5% dimethyl sulfoxide, 25% polyethylene glycol 300 and 70% distilled water; 2) 0.1 mg / kg methyl. 3,5-Diphenylpyridazine-4-carboxylate; 3) 0.3 mg / kg of methyl 3,5-diphenylpyridazine-4-carboxylate; 4) 1 mg / kg of methyl 3,5-diphenylpyridazine-4-carboxylate Rate); and 5) Pretreatment with injection by one intraperitoneal (ip) injection of 3 mg / kg methyl 3,5-diphenylpyridazine-4-carboxylate. Injections were given every other day with a drug holiday in between. Each AI rat was treated under all 5 conditions within the test period. To offset any potential bias, an ascending-descending dose series, i.e., a series of doses, first administered in ascending order and then repeated in descending order, the effect of the drug. Was evaluated. Therefore, each dose was measured twice.

Using parametric statistics (paired t-test), AI rats in a 2-hour delay time version of the RAM task in the context of various doses of methyl 3,5-diphenylpyridazine-4-carboxylate and vehicle control. The results of the inscription inspection were compared (see Fig. 1). The average number of errors that occurred during the trial was 3 mg / kg of methyl 3, compared to when the vehicle control was used (mean number of errors ± standard error of mean (SEM) = 3.13 ± 0.62). Significantly less in 5-diphenylpyridazine-4-carboxylate treatment (mean number of errors ± SEM = 1.31 ± 0.40). Methyl 3,5-diphenylpyridazine-4-carboxylate significantly improved memory capacity at 3 mg / kg compared to vehicle control treatment (t (7) = 4.233, p = 0.004).

When treated simultaneously with the AI rats are α5 containing GABA _A R inverse agonists of 0.3mg / kg TB21007, therapeutic dose of 3 mg / kg was disabled. When TB21007 / methyl 3,5-diphenylpyridazine-4-carboxylate combination treatment (0.3 mg / kg TB21007 in combination with 3 mg / kg methyl 3,5-diphenylpyridazine-4-carboxylate) was used. The average number of errors made by rats was 2.88 ± 1.32, which was not different from that of rats treated with vehicle control (average number of errors of 3.13 ± 1.17). Therefore, the effect of methyl 3,5-diphenylpyridazine-4-carboxylate on spatial memory is a GABA _A α5 receptor-dependent effect (see FIG. 1).
(B) Effect of methyl 3,5-diphenylpyridazine-4-carboxylate on α5-containing GABA _{A receptor occupancy Animals}

Adult male Long Evans rats (265-295 g, Charles River, Portage, MI, n = 4 / group) were _{used for GABA A} α5 receptor occupancy studies. Rats were individually housed in a ventilated stainless steel rack at 12:12 light / dark. Food and water were freely available. Further studies assessing exposure of the compound at behaviorally active doses used young or aged Long Evan rats (n = 2-4 / group) for these studies.
Compound

Ro15-4513 was used as a receptor occupancy (RO) tracer for _{GABA A} α5 receptor sites in the hippocampus and cerebellum. Based on the selectivity of Ro15-4513 for _{the GABA A} α5 receptor when compared to other alpha subunit-containing GABA _A receptors, and Ro15-4513 successfully used for _{GABA A α5 RO studies in animals and humans.} (For example, Lingford-Huges et al., J. Cerev. Blood Flow Meterab. 22: 878-89 (2002); Pym et al., Br. J. Pharmacol. 146: 817-825 (2005); and Maeda et al. , Synapse 47: 200-208 (2003)), Ro15-4513 was selected as the tracer. Ro15-4513 (1 μg / kg) was dissolved in 25% hydroxyl-propyl beta-cyclodextrin and i.I. 20 minutes prior to RO evaluation. v. It was administered. Methyl 3,5-diphenylpyridazine-4-carboxylate (0.1-10 mg / kg) was synthesized by Nox Pharmaceuticals (India), dissolved in 25% hydroxyl-propylbeta-cyclodextrin and injected by tracer. 15 minutes ago i. v. It was administered. Compounds are 0.5 ml / kg, except for the highest dose of methyl 3,5-diphenylpyridazine-4-carboxylate (10 mg / kg) administered in a volume of 1 ml / kg due to solubility limits. Was administered in the volume of.
Tissue preparation and analysis

Twenty minutes after the tracer injection, the rats were sacrificed by cervical dislocation. The whole brain was quickly removed and rinsed lightly with sterile water. Trunk blood was collected in EDTA-coated Eppendorf tubes and stored on wet ice until the study was completed. The hippocampus and cerebellum were resected and stored in a 1.5 ml Eppendorf tube and stored on wet ice until tissue extraction. In drug-untreated rats, 6 cortical brain tissue samples were collected for use in preparing blank and calibration curve samples.

Acetonitrile containing 0.1% formic acid was added to each sample in a volume four times the weight of the tissue sample. For calibration curve (0.1 to 30 ng / g) samples, the calculated volume of standard material reduced the volume of acetonitrile. The sample is homogenized (FastPrep-24, Lysing Matrix D; 5.5 m / s, 60 seconds, or 7-8 watts of force using a sonic probe dismemberer; Fisher Scientific) for 16 minutes at 14,000 rpm. Centrifuged. The (100 μl) supernatant solution was diluted with 300 μl sterile water (pH 6.5). The solution was then thoroughly mixed and analyzed by LC / MS / MS for Ro15-4513 (tracer) and methyl 3,5-diphenylpyridazine-4-carboxylate.

For plasma exposure, blood samples were centrifuged at 14000 rpm for 16 minutes. After centrifugation, 50 ul of supernatant (plasma) from each sample was added to 200 μl of acetonitrile + 0.1% formic acid. For calibration curve (1-1000 ng / ml) samples, the calculated volume of standard material reduced the volume of acetonitrile. The sample was sonicated in an ultrasonic water bath for 5 minutes and then centrifuged at 16000 RPM for 30 minutes. After removing 100 ul of the supernatant from each sample vial and placing it in a new glass auto sample vial, 300 μl of sterile water (pH 6.5) was added. The solution was then thoroughly mixed and analyzed by LC / MS / MS for methyl 3,5-diphenylpyridazine-4-carboxylate.

By a _{rational method comparing occupancy in the hippocampus (regions with high GABA A} α5 receptor density) to occupancy in the cerebral brain ( _{regions with low density of GABA A} α5 receptors), and further, high doses of GABA to define complete occupancy. _{Receptor occupancy was measured with A} α5 negative allosteric modulator L-655,708 (10 mg / kg, iv).

After administration of the vehicle, 1 μg / kg, i. v. By administering the Ro15-4513 tracer, the level of Ro15-4513 is> 5 times higher in the hippocampus (1.93 ± 0.05 ng / g) than in the cerebellum (0.36 ± 0.02 ng / g). It was brought. Methyl 3,5-diphenylpyridazine-4-carboxylate (0.01-10 mg / kg, iv) did not affect the cerebellar levels of Ro15-4513 (FIG. 2), but Ro15-4513 in the hippocampus. Binding was reduced dose-dependently, 10 mg / kg, i. v. Dose showed> 90% occupancy (Fig. 3). Both methods of calculating RO yield very similar results, and is the ED50 value for methyl 3,5-diphenylpyridazine-4-carboxylate 1.8 mg / kg based on the ratio method? , Or when L-755,608 was used to define occupancy, it was 1.1 mg / kg.

Methyl 3,5-diphenylpyridazine-4-carboxylate exposure was 0.01 mg / kg in both plasma and hippocampus, i. v. Although it was below the limit of quantification (BQL), 0.1 mg / kg, i. In v, it was detectable at low levels in the hippocampus (see Table 3). Hippocampal exposure was 0.1 to 1 mg / kg, i. v. It was linear as a 10-fold increase at the dose of, resulting in a 12-fold increase in exposure. 1 to 10 mg / kg, i. v. Simply increasing the dose increased the exposure by about 5-fold. Plasma exposure is at doses of 1 to 10 mg / kg, i. v. When it increased to, it increased 12 times.

Further studies were performed in aged Long-Evans rats to measure exposure at behaviorally reasonable doses in cognitive studies. Exposure in young Long-Evans rats was also measured to bridge the receptor occupancy studies performed in young Long-Evans rats. Exposures in young and aged Long-Evans rats were relatively similar (Table 4, Figure 4). A 3-fold increase in dose from 1 to 3 mg / kg, ip results in an increase in exposure in both hippocampus and plasma in young and aged rats that is greater than the dose-proportional increase. It was in the range of 5 to 6.6 times.

In this RO study, exposure to 180 ng / g in the hippocampus (1 mg / kg, iv) corresponded to 32-39% receptor occupancy, depending on the method used to measure RO. This exposure was 3 mg / kg, i. p. Similar to what is observed in aged rats in, suggests that 30-40% RO is required for cognitive efficacy in this model.

These studies demonstrated that methyl 3,5-diphenylpyridazine-4-carboxylate _{increased GABA A} a5 receptor occupancy in a dose-dependent manner. Methyl 3,5-diphenylpyridazine-4-carboxylate also showed good brain exposure with a> 1 brain / plasma ratio. These studies, methyl 3,5-diphenyl-4-carboxylate, was further demonstrated that has brought the cognitive improvement by a positive allosteric modulation of GABA A _a5 subtype receptors.
Example 108: Ethyl 3-methoxy-7-methyl-9H-benzo [f] imidazo [1,5-a] [1,2,4] triazolo [4,3-d] [ 1,4] Effect of diazepine-10-carboxylate

Achermann et al., Bioorg. Med. Chem. Let. , 19: 5746-575 (2009), corresponding to compound number 49, ethyl 3-methoxy-7-methyl-9H-benzo [f] imidazo [1,5-a] [1,2,4] triazolo [4, 3-d] [1,4] diazepin-10-carboxylate is a selective α5 containing GABA _a R agonists.

Ethyl 3-methoxy-7-methyl-9H-benzo [f] imidazo [1,5-a] [1,2,4] triazolo [4,3-d] for in vivo spatial memory retention in aging disorder (AI) rats [1,4] The effects of diazepine-10-carboxylate were tested on vehicle control (25% cyclodextrin, which was tested 3 times: at the beginning, middle and end of the ascending / descending series) and 6 different dose levels (0). .1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg and 30 mg / kg, each dose was tested twice) ethyl 3-methoxy-7-methyl-9H-benzo [f] ] Imidazo [1,5-a] [1,2,4] triazolo [4,3-d] [1,4] diazepine-10-carboxylate, as described in Example 107 (A). Evaluated in a radial maze (RAM) behavioral task that is essentially similar to such a task. Same vehicle control and same dose of ethyl 3-methoxy-7-methyl-9H-benzo [f] imidazole [1,5-a] [1,2,4] triazolo [4,3-d] [1,4] The same experiment was repeated using diazepine-10-carboxylate. In that experiment, vehicle control was tested 5 times and at a dose of 3 mg / kg ethyl 3-methoxy-7-methyl-9H-benzo [f] imidazo [1,5-a] [1,2,4] triazolo. [4,3-d] [1,4] diazepine-10-carboxylate was tested four times and other doses of ethyl 3-methoxy-7-methyl-9H-benzo [f] imidazole [1,5-]. a] [1,2,4] triazolo [4,3-d] [1,4] diazepine-10-carboxylate was tested twice.

Using parametric statistics (paired t-test), various doses of ethyl 3-methoxy-7-methyl-9H-benzo [f] imidazo [1,5-a] [1,2,4] triazolo [ 4,3-d] [1,4] Compared the performance of AI rat memorization tests in a 4-hour delay time version of the RAM task in the context of diazepine-10-carboxylate and vehicle control (see Figure 5). That). Ethyl 3-methoxy-7-methyl-9H-benzo [f] imidazo [1,5-a] [1,2,4] triazolo [4,3-d] [1,4] compared to vehicle control treatment Diazepine-10-carboxylate is 3 mg / kg (t (7) = 4.13, p = 0.004 or t (7) = 3.08, p = 0.018) and 10 mg / kg (t (7)). ) = 2.82, p = 0.026) significantly improved memory capacity.

Ethyl 3-methoxy-7-methyl-9H-benzo [f] imidazo [1,5-a] [1,2,4] triazolo [4,3-d] [1,4] for α5-containing GABA _{A receptor occupancy} The effect of diazepine-10-carboxylate was also investigated according to a procedure essentially similar to that described in Example 107 (B) (see above). From this study, ethyl 3-methoxy-7-methyl-9H-benzo [f] imidazole [1,5-a] [1,2,4] triazolo [4,3-d] [1,4] diazepine-10 -Carboxylate (0.01-10 mg / kg, iv) reduces the binding of Ro15-4513 in the hippocampus without affecting the cerebral levels of Ro15-4513 (FIG. 6), 10 mg / kg, i. .. v. It was demonstrated that the dose of was> 90% occupied (Fig. 7).
Example 109: 6,6dimethyl-3- (3-hydroxypropyl) thio-1- (thiazole-2-yl) -6,7-dihydro-2 in elderly disabled rats with the Maurice water maze behavioral task -Benzothiophene-4 (5H) -Effect of on

Chambers et al., J. Mol. Med. Chem. 46: 6-6dimethyl-3- (3-hydroxypropyl) thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophene corresponding to compound 44 in 2227-2240 (2003). 4 (5H) - on is a selective α5 containing GABA _a R agonists.

6,6dimethyl-3- (3-hydroxypropyl) thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophene-4 (6,6dimethyl-3- (3-hydroxypropyl) thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophene-4 (3) for in vivo spatial memory retention in aging disorder (AI) rats 5H) -The effect of on was evaluated in the Maurice water maze behavior task. A water maze is a pool surrounded by a new pattern set for the maze. The training protocol for this water maze has been shown to be hippocampal-dependent modified water maze task (de Hoz et al., Eur. J. Neurosci., 22: 745-54, 2005; Steele and Morris, Hippocampus 9: 118- 36, 1999).

A unilateral cannula was inserted into the lateral ventricle of a cognitively impaired elderly rat. The localization coordinates were 1.0 mm posterior to the bregma, 1.5 mm lateral to the midline and 3.5 mm ventral to the cranial surface. After approximately a week of recovery, rats were pre-trained in a water maze for two days (six trials per day) to locate an escape platform hidden beneath the surface of the pool. , The location of the escape platform changed day by day. No intraventricular (ICV) injection was performed during pre-training.

After pre-training, rats were charged with 100 μg of 6,6dimethyl-3- (3-hydroxypropyl) thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophene in 5 μl DMSO. Either -4 (5H) -on (n = 6) or vehicle DMSO (n = 5) was infused with ICV 40 minutes prior to water labyrinth training and testing. The training consisted of eight tests per day for two days, leaving the hidden escape platform in the same position. Rats were given 60 seconds to locate the platform, with a 60 second interval between trials. The rats were subjected to a probe test (120 seconds) with the escape platform removed 24 hours after the end of training. The training was divided into 4 blocks, and 4 training trials were performed in each block.

Rats treated with vehicle and 6,6 dimethyl-3- (3-hydroxypropyl) thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophen-4 (5H) -one At the beginning of the training, I found an escape platform almost at the same time (Block 1). In this training block, with vehicle and 6,6 dimethyl-3- (3-hydroxypropyl) thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophene-4 (5H) -on. Both treated rats spent about 24 seconds finding an escape platform. However, rats treated with 6,6 dimethyl-3- (3-hydroxypropyl) thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophen-4 (5H) -one At the end of training (block 4), we were able to find a better (ie, faster) platform than rats treated with vehicle alone. Block 4 was treated with 6,6 dimethyl-3- (3-hydroxypropyl) thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophen-4 (5H) -one. Rats spent about 9.6 seconds finding an escape platform, whereas vehicle-treated rats spent about 19.69 seconds. From these results, 6,6dimethyl-3- (3-hydroxypropyl) thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophene-4 (5H) -one was added to the rat. It is suggested that the learning of the water maze task was improved in (see FIG. 8 (A)).

In the inspection trial 24 hours after training, the escape platform was removed. The rat search / swimming pattern was used to determine if the rat remembered where the escape platform was located during pretrial training to test the rat's long-term memory. In this trial, the "target ring" is the designated area around the area where the platform was located during pretrial training, 1.5 times the size of the escape platform. The "opposite ring" is a control area of the same size as the target ring and is located opposite the target ring in the pool. If the rat has good long-term memory, the rat is in the area surrounding the location where the platform was located during pretrial training (ie, in a "target" ring; "opposite" ring. There may be a tendency to search for). "Time spent in the ring" is the length of time, in seconds, that the rat spends in the target ring or contralateral ring area. The "number of crossings" of the ring is the number of times the rat swims across the target ring or contralateral ring area.

Rats treated with the vehicle spent the same length of time in the target and contralateral toroids, suggesting that these rats do not remember where the platform was during pretrial training. It was suggested that In contrast, it was treated with 6,6 dimethyl-3- (3-hydroxypropyl) thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophen-4 (5H) -one. Rats spent significantly longer time in the target ring and more frequently crossed the "target ring" compared to the time spent in the "opposite ring" or the number of crossings in the "opposite ring". .. From these results, 6,6dimethyl-3- (3-hydroxypropyl) thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophene-4 (5H) -one was added to the water. It is suggested that the long-term memory of the rat was improved in the maze task (see FIGS. 8 (B) and 8 (C)).

The compounds of the present invention _{showed a positive allosteric regulatory effect on the GABA A} α5 receptor (see, eg, Example 106). These compounds may enhance the effect of GABA on the _{GABA A α5 receptor.} Therefore, the compounds of the present invention are used in other GABA _A α5 receptor-selective agonists (eg, methyl 3,5-diphenylpyridazine-4-carboxylate, ethyl 3-methoxy-7-) in aged disabled animals (eg, rats). Methyl-9H-benzo [f] imidazo [1,5-a] [1,2,4] triazolo [4,3-d] [1,4] diazepine-10-carboxylate and 6,6 dimethyl-3- Effects brought about by (3-hydroxypropyl) thio-1- (thiazole-2-yl) -6,7-dihydro-2-benzothiophen-4 (5H) -one) (see, eg, Examples 28-30). It should bring about the same cognitive enhancement effect as (that).

Claims (26)

Formula II or IV:

Compound, or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, Z (zusammen) isomer, E (entgegen) isomer, or tautomer thereof. :
When the compound has the structure of formula IV, R ² is -OR ⁸ , -SR ⁸ ,-(CH ₂ ) _n OR ⁸ ,-(CH ₂ ) _n O (CH ₂ ) _n R ⁸ , and-( CH ₂ ) _n N (R'') R ¹⁰ ; where R ² is independently substituted with 0-5 R';
m and n are integers independently selected from 0 to 4;
The ^{existence of R 1} , R ² , R ⁴ , and R ⁵ is independent of each other:
Halogen, -R, -OR, -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ , -SiR ₃ , -N (R) ₂ , -SR, -SOR, -SO ₂ R, -SO ₂ N (R) ₂ , -SO ₃ R,-(CR ₂ ) _1-3 R,-(CR ₂ ) _1-3- OR,-(CR ₂ ) _0-3 -C (O) NR (CR ₂₎ ) _0-3 R,-(CR ₂ ) _0-3 -C (O) NR (CR ₂ ) _0-3 OR, -C (O) R, -C (O) C (O) R, -C ( O) CH ₂ C (O) R, -C (S) R, -C (S) OR, -C (O) OR, -C (O) C (O) OR, -C (O) C (O) ) N (R) ₂ , -OC (O) R, -C (O) N (R) ₂ , -OC (O) N (R) ₂ , -C (S) N (R) ₂ ,-(CR) ₂ ) _{0 to 3} NHC (O) R, -N (R) N (R) COR, -N (R) N (R) C (O) OR, -N (R) N (R) CON (R) ₂ , -N (R) SO ₂ R, -N (R) SO ₂ N (R) ₂ , -N (R) C (O) OR, -N (R) C (O) R, -N (R) ) C (S) R, -N (R) C (O) N (R) ₂ , -N (R) C (S) N (R) ₂ , -N (COR) COR, -N (OR) R , -C (= NH) N (R) ₂ , -C (O) N (OR) R, -C (= NOR) R, -OP (O) (OR) ₂ , -P (O) (R) ₂ , -P (O) (OR) ₂ , and -P (O) (H) (OR);
R ³ is a 5- to 10-membered heteroaryl-and the heteroaryl has 1 to 4 heteroatoms independently selected from N, NH, O, and S; here. So, R ³ is independently replaced by 0-5 R';
R ⁶ is, -H or - be (C1 -C6) alkyl;
Each R ⁸ is independently a-(C1-C6) alkyl,-(C3-C10) -cycloalkyl, (C6-C10) -aryl, or 5- to 10-membered heteroaryl, where R ^{8 is.} Each existence of is independently replaced by 0-5 R';
Each R ¹⁰ is independently a-(C3-C10) -cycloalkyl, 3-member to 10-membered heterocyclyl-, (C6-C10) -aryl, or 5- to 10-membered heteroaryl, where R ^{Each of the 10} beings is independently replaced by 0-5 R';
Each R is independent:
H-,
(C1-C12) -aliphatic-,
(C3 to C10) -Cycloalkyl-,
(C3 to C10) -Cycloalkenyl-,
[(C3 to C10) -cycloalkyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkyl] -O- (C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl] -O- (C1 to C12) -aliphatic-,
(C6 to C10) -aryl-,
(C6 to C10) -aryl- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-O- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-N (R'')-(C1 to C12) aliphatic-,
Heterocyclyl of 3 to 10 members-,
(3-10 member heterocyclyl)-(C1-C12) Aliphatic-,
(3-10 member heterocyclyl) -O- (C1-C12) aliphatic-,
(3-10 member heterocyclyl) -N (R'')-(C1-C12) aliphatic-,
5-10 member heteroaryl-,
(5- to 10-membered heteroaryl)-(C1-C12) -aliphatic-,
(5-membered to 10-membered heteroaryl) -O- (C1-C12) -aliphatic-; and (5-membered to 10-membered heteroaryl) -N (R'')-(C1-C12) -aliphatic −
Selected from;
Here, the heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO ₂ , and the heteroaryl is N, NH, O,. And has 1 to 4 heteroatoms selected independently of S;
Where each existence of R is independently replaced by 0-5 R';
Alternatively, if two R groups are attached to the same atom, the two R groups, together with the atom to which they are attached, are N, NH, O, S, SO, and SO _2. Can form a 3- to 10-membered aromatic or non-aromatic ring with 0-4 heteroatoms selected independently from, where the ring is 0-5 R'. The ring is optionally substituted with, and the ring is required for (C6-C10) aryl, 5-membered to 10-membered heteroaryl, (C3-C10) cycloalkyl, or 3-membered to 10-membered heterocyclyl. Condensed accordingly;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, -CH ₂ OR " _{, -CH 2} NR" ₂ , and -C (O) N (R'. ') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R') ₂ ;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl,-(C1-C6) -aryl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl. 5, 10-membered heteroaryl-, (C6-C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1) ~ C6) -alkyl-, (5-member to 10-membered heteroaryl) -O- (C1-C6) -alkyl-, and (C6-C10) -aryl-O- (C1-C6) -alkyl- Here, each presence of R'' is halogen, -R ^o , -OR ^o , oxo, -CH ₂ OR ^o , -CH ₂ N (R ^o ) ₂ , -C (O) N (R ^o ). _{^{2, -C (O) oR o}} , -NO 2, -NCS, -CN, -CF 3, independently at 0-3 substituents selected from -OCF _3, and -N ^(R _{o) 2} It is substituted Te, wherein each occurrence of ^{R o} is independently, - (C1 -C6) - aliphatic, (C3 -C6) - cycloalkyl, 3-6 membered heterocyclyl, 5- to 10-membered Heteroaryl-and (C6-C10) -aryl-selected from
A compound or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, Z (zusammen) isomer, E (entgegen) isomer, or tautomer thereof. Equation II:

Compound, or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, Z (zusammen) isomer, E (entgegen) isomer, or tautomer thereof of the formula II. In:
m is 0 to 3;
Each R ¹ is independently a halogen, -H,-(C1-C6) alkyl, -OH, -O ((C1-C6) alkyl), -NO ₂ , -CN, -CF ₃ , and -OCF ₃ Selected from, where R ¹ is independently replaced by 0-5 R';
R ² is:
-H, Halogen,-(C1-C6) alkyl, -OH, -O ((C1-C6) alkyl), -C (O) O ((C1-C6) alkyl), -C (O) NR ₂ ,
(C6 to C10) -aryl-,
(C6 to C10) -aryl- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-O- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-N (R'')-(C1 to C12) aliphatic-,
(5- to 10-membered heteroaryl)-(C1-C12) aliphatic-,
(5- to 10-membered heteroaryl) -O- (C1-C12) aliphatic-,
(5- to 10-membered heteroaryl) -N (R'')-(C1-C12) aliphatic-,
(3-10 member heterocyclyl)-(C1-C12) Aliphatic-,
(3-10 member heterocyclyl) -O- (C1-C12) aliphatic-and (3-10 member heterocyclyl) -N (R'')-(C1-C12) aliphatic-
Selected from
Here R ² is independently replaced by 0-5 R';
R ³ is a 5-membered to 10-membered heteroaryl, wherein ^{R 3} is independently is substituted with 0 to five R ';
R ⁴ and R ⁵ are independently selected from -H, halogen and-(C1-C6) alkyl;
R ⁶ is, -H and - is selected from (C1 -C6) alkyl;
Each R is independent:
H-,
(C1-C12) -aliphatic-,
(C3 to C10) -Cycloalkyl-,
(C3 to C10) -Cycloalkenyl-,
[(C3 to C10) -cycloalkyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl]-(C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkyl] -O- (C1 to C12) -aliphatic-,
[(C3 to C10) -cycloalkenyl] -O- (C1 to C12) -aliphatic-,
(C6 to C10) -aryl-,
(C6 to C10) -aryl- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-O- (C1 to C12) aliphatic-,
(C6 to C10) -aryl-N (R'')-(C1 to C12) aliphatic-,
Heterocyclyl of 3 to 10 members-,
(3-10 member heterocyclyl)-(C1-C12) Aliphatic-,
(3-10 member heterocyclyl) -O- (C1-C12) aliphatic-,
(3-10 member heterocyclyl) -N (R'')-(C1-C12) aliphatic-,
5-10 member heteroaryl-,
(5- to 10-membered heteroaryl)-(C1-C12) -aliphatic-,
(5-membered to 10-membered heteroaryl) -O- (C1-C12) -aliphatic-; and (5-membered to 10-membered heteroaryl) -N (R'')-(C1-C12) -aliphatic −
Selected from;
Here, the heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO ₂ , and the heteroaryl is N, NH, O,. And has 1 to 4 heteroatoms selected independently of S;
Where each existence of R is independently replaced by 0-5 R';
Alternatively, if two R groups are attached to the same atom, the two R groups, together with the atom to which they are attached, are N, NH, O, S, SO, and SO _2. Can form a 3- to 10-membered aromatic or non-aromatic ring with 0-4 heteroatoms selected independently from, where the ring is 0-5 R'. The ring is optionally substituted with, and the ring is required for (C6-C10) aryl, 5-membered to 10-membered heteroaryl, (C3-C10) cycloalkyl, or 3-membered to 10-membered heterocyclyl. Condensed accordingly;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, -CH ₂ OR " _{, -CH 2} NR" ₂ , and -C (O) N (R'. ') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R') ₂ ;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-. , (C6 to C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1-C6) -alkyl-, (5-membered) Selected from 10-membered heteroaryl) -O- (C1-C6) -alkyl- and (C6-C10) -aryl-O- (C1-C6) -alkyl-.
A compound or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, Z (zusammen) isomer, E (entgegen) isomer, or tautomer thereof. Equation IV:

Compound, or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, Z (zusammen) isomer, E (entgegen) isomer, or tautomer thereof of the formula IV. In:
m is 0 to 3;
Each R ¹ is independently halogen, -H,-(C1-C6) alkyl, -C≡CH, -OH, -O ((C1-C6) alkyl), -NO ₂ , -CN, -CF ₃ , -OCF ₃ where R ¹ is independently replaced with 0-5 R';
R ² is −OR ⁸ , −SR ⁸ , − (CH ₂ ) _n OR ⁸ , − (CH ₂ ) _n O (CH ₂ ) _n R ⁸ , and − (CH ₂ ) _n N (R'') R. ^{Selected from 10} where n is an integer selected from 0 to 4; p is an integer selected from 2 to 4; each R ⁸ is independently − (C1 to C6) alkyl. , - (C3 -C10) - cycloalkyl, (C6-C10) - aryl, or a 5- to 10-membered heteroaryl, wherein each occurrence of ^{R 8} is independently 0 to five R It is substituted with '; each ^{R 10} is independently, - (C3 -C10) - cycloalkyl, 3-membered to 10-membered heterocyclyl -, (C6-C10) - aryl or 5-membered to 10-membered heterocyclic, Aryl, where ^{each presence of R 10} is independently substituted with 0-5 R'; where R ² is independently substituted with 0-5 R'. Aryl;
R ³ is 5-membered or 6-membered heteroaryl; wherein R ³ is independently is substituted with 0 to five R ';
R ⁴ and R ⁵ are independently selected from -H, halogen and-(C1-C6) alkyl;
R ⁶ is, -H and - is selected from (C1 -C6) alkyl;
Here, each existence of R'is independent of halogen, -R ", -OR", oxo, -CH ₂ OR " _{, -CH 2} NR" ₂ , and -C (O) N (R'. ') ₂ , -C (O) OR'', -NO ₂ , -NCS, -CN, -CF ₃ , -OCF ₃ and -N (R') ₂ ;
Here, each presence of R'' is independently H,-(C1-C6) -alkyl, (C3-C6) -cycloalkyl, 3- to 6-membered heterocyclyl, 5-membered to 10-membered heteroaryl-. , (C6 to C10) -aryl-, (5-membered to 10-membered heteroaryl)-(C1-C6) -alkyl-, (C6-C10) -aryl- (C1-C6) -alkyl-, (5-membered) Selected from 10-membered heteroaryl) -O- (C1-C6) -alkyl- and (C6-C10) -aryl-O- (C1-C6) -alkyl-.
A compound or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, Z (zusammen) isomer, E (entgegen) isomer, or tautomer thereof.

A compound selected from, or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, Z (zusammen) isomer, E (entgegen) isomer, or tautomer thereof.

A compound selected from, or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, Z (zusammen) isomer, E (entgegen) isomer, or tautomer thereof. A therapeutically effective amount of the compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, Z (zusammen) isomer, E (entgegen) thereof. ) An isomer, or tautomer; and a pharmaceutical composition comprising an acceptable carrier, adjuvant or vehicle. The pharmaceutical composition according to claim 6, wherein the composition further comprises a second therapeutic agent. The pharmaceutical composition according to claim 7, wherein the second therapeutic agent is selected from antipsychotic agents, memantine and acetylcholinesterase inhibitors (AChE-I). The second therapeutic agent is the antipsychotic agent selected from aripiprazole, olanzapine and ziprasidone and pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof, according to claim 7. Pharmaceutical composition. The pharmaceutical composition of claim 7, wherein the second therapeutic agent is memantine, a pharmaceutically acceptable salt thereof, a hydrate, a solvate or a polymorph. The second therapeutic agent is AChE-I selected from donepezil, galantamine and rivastigmine and pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof, according to claim 7. Pharmaceutical composition. A composition comprising the compound according to any one of claims 1 to 5, or a pharmaceutical composition according to any one of claims 6 to 11, wherein a central nervous system (CNS) disorder or is present. A composition or pharmaceutical composition for treating central nervous system (CNS) disorders or cognitive disorders associated with cancer treatment in subjects requiring treatment of cognitive disorders associated with the treatment of cancer. The composition or pharmaceutical composition of claim 12, wherein the cognitive impairment is associated with age-related cognitive impairment. The composition or pharmaceutical composition according to claim 13, wherein the age-related cognitive impairment is mild cognitive impairment (MCI). The composition or pharmaceutical composition according to claim 14, wherein the mild cognitive impairment is amnestic mild cognitive impairment (aMCI). The composition or pharmaceutical composition according to claim 12, wherein the CNS disorder is dementia. The composition or pharmaceutical composition according to claim 16, wherein the dementia is Alzheimer's disease. The composition or pharmaceutical composition according to claim 12, wherein the CNS disorder is schizophrenia or bipolar disorder. The composition or pharmaceutical composition according to claim 12, wherein the CNS disorder is amyotrophic lateral sclerosis (ALS). The composition or pharmaceutical composition according to claim 12, wherein the CNS disorder is post-traumatic stress disorder (PTSD). The composition or pharmaceutical composition according to claim 12, wherein the CNS disorder is mental retardation. The composition or pharmaceutical composition according to claim 12, wherein the CNS disorder is Parkinson's disease (PD). The composition or pharmaceutical composition according to claim 12, wherein the CNS disorder is autism. The composition or pharmaceutical composition according to claim 12, wherein the CNS disorder is obsessive-compulsive behavior. The composition or pharmaceutical composition according to claim 12, wherein the CNS disorder is a substance addiction. A composition containing the compound according to any one of claims 1 to 5 for use as a pharmaceutical.

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